Patent application title: Delivering polypeptides to phagocytes
Inventors:
Jeffrey N. Sfakianos (Burlingame, CA, US)
IPC8 Class: AC12N1511FI
USPC Class:
4241841
Class name: Drug, bio-affecting and body treating compositions antigen, epitope, or other immunospecific immunoeffector (e.g., immunospecific vaccine, immunospecific stimulator of cell-mediated immunity, immunospecific tolerogen, immunospecific immunosuppressor, etc.)
Publication date: 2013-11-28
Patent application number: 20130315938
Abstract:
The current invention is a particle comprising an assembly of
lipid-enveloped core polypeptides and transmembrane polypeptides. The
transmembrane polypeptides comprise sequences that bind to phagocytes
through indirect or direct binding by surface receptors. The result of
transmembrane polypeptide binding is engulfment by the phagocyte to
low-pH compartments. The low pH triggers a conformational change in
transmembrane polypeptides whereby lipids of particles and phagocytes are
fused and the contents of the particle, including a polypeptide to be
delivered to the cell, are released into the phagocyte.Claims:
1. Isolated nucleic acids comprising sequences encoding polypeptides that
assemble to form lipid-enveloped particles that are targeted to the
cytoplasm of phagocytes.
2. The nucleic acids of claim 1 operably linked to expression control sequences.
3. A cultured cell comprising the nucleic acids of claim 2.
4. The isolated nucleic acids of claim 1 encoding core polypeptides that assemble to form particles containing polypeptides to be delivered to phagocytes.
5. The isolated nucleic acids of claim 1 comprising sequences encoding polypeptides that assemble to form lipid-enveloped particles, wherein the encoded polypeptides are transmembrane polypeptides.
6. The isolated particles of claim 1 that have been separated from producer cells.
7. A pharmaceutical preparation of the isolated particles of claim 6 wherein the product is useful in therapy or vaccination.
8. (canceled)
9. A kit comprising the nucleic acids of claim 1.
Description:
RELATED U.S. APPLICATION DATA
[0001] U.S. Pat. No. 6,294,165--2001 Sep. 25, Andrew Michael Lindsay Lever and Eric Hunter.
[0002] U.S. Pat. No. 5,747,307--1998 May 5, Andrew Michael Lindsay Lever and Eric Hunter.
[0003] U.S. Pat. No. 5,849,586--1998 Dec. 15, Michael Kriegler and Carl F. Perez.
BACKGROUND
[0004] Biologicals, consisting of polypeptides or nucleic acids, are used therapeutically to alter the behavior of cells. For example, insulin increases the cellular uptake of glucose and anti-EGFR reduces the rate of cellular replication. The polypeptides are also used to treat diabetics and cancer. Further, expression of exogenous nucleic acids are being developed as gene therapies for numerous diseases. However, cells have evolved as lipid-bound compartments where the types of molecules moving across lipids, and thus between compartments, is stringently regulated. The initial regulation occurs at a limiting plasma membrane that separates the outside of the cell from the inner molecules and organelles. While the plasma membrane is semipermeable, the molecules that are allowed to cross have exquisitely co-evolved with transport molecules or satisfy a strict range of hydrophobicity profiles. Thus, biological-based therapies are currently restricted to targeting those molecules accessible from the outside of the cell. Of the examples stated above, insulin and anti-EGFR bind to the extracellular domain of transmembrane receptors and signal pathways are activated to convey the binding event to the inside of cells. Unfortunately, extracellular domains represent a minority of gene products potentially targeted with biologicals.
[0005] Accessing the inside of cells requires special packaging into vectors that allows penetration across the plasma membrane. However, vectors frequently forgo specificity of targeting particular cell types and are often immunogenic. While targeting specific cells is necessary for effective therapy, the latter problem often precludes development of solutions to the prior. When vector-based biologicals are administered to an organism, the host immune system develops antibodies to domains on the outside of the vector. Upon subsequent uses, particles or components thereof are opsonized. Opsonization involves coating with antibodies, engulfment by phagocytes, and then degradation. This process effectively decreases available vectors or doses. Efforts to overcome this problem by increasing doses promotes sepsis, leading to painful toxicity and sometimes death (N. Engl. J. Med. (2003)348:255-256 and Mol. Gen. Metab. (2003)80:148-158). Thus, the field has commonly viewed the host immune system as an obstacle to using biologicals.
[0006] For the foregoing reasons, which are not admitted to be prior art with respect to any version of the present invention by its mention in the background, there is a strong need for gaining access to the inside of cells with specificity in the cell types targeted, while avoiding the detriments imposed by a subject's immune system.
SUMMARY
[0007] The invention described herein are nucleic acids encoding polypeptides packaged into lipid-enveloped particles and delivered specifically to phagocytes through direct and indirect mechanisms. A current need in the science is satisfied by including transmembrane polypeptides on the surface of the particles to mediate delivery to a specific cell type. Delivery of biologicals is by binding to receptors on the surface of phagocytes whereby engulfment of particles occur. Particles also comprise transmembrane polypeptides that facilitate movement of contents of the particles from engulfment compartments into the cytoplasm. The result is delivery of biological-based molecules to specific cell types.
[0008] The described particles could be used for a multitude of purposes including to promote wound healing, reduce atherosclerotic plaques, subside allergic reactions, stimulate immunity through vaccination, treat liver diseases, or to slow the effects of aging.
DESCRIPTIONS OF THE DRAWINGS
[0009] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, appended claims, and accompanying drawings where:
[0010] FIG. 1 shows a schematic of two categories of polypeptides of claim 1 and domains comprising the sequences. Organization of the domains represents the most preferred order, but other organizations may be used. Separate domains are represented with different patterns. (A) The first category are core polypeptides. Each particle comprises one or more of a plurality of core polypeptides. The core polypeptides of claim 1 comprise a lipid-binding domain (LBD), an interaction domain (I domain), a late domain (L domain), a protease domain (Pro), and a polypeptide to be delivered (p2bd). Sequences between domains comprise sequences that can be hydrolyzed by a chemical or an enzyme. (B) The nucleic acids encoding core polypeptides may use a ribosomal frame shift sequence to express domains on portions of translated core polypeptides. The schematic shows use of a ribosomal frame shift to express a core polypeptide whereby a portion of core polypeptides comprise a Pro domain. (C-G) The second category is transmembrane polypeptides. Transmembrane polypeptides comprise domains so that particles of claim 1 target low-pH compartments of phagocytes and fuse lipids of particles and phagocytes. Each particle may comprise one or more of a plurality of transmembrane polypeptides. Transmembrane polypeptides comprise a signal peptide domain (sig pep), a membrane spanning domain (msd), a cytoplasmic domain (cyto domain), and an extracellular domain. The extracellular domain comprises a low pH fusion domain, an antibody domain, a complement domain, a sequence recognized by the host immune system, or a combination or fragment thereof. Sequences of these domains may comprise fragments or mutations. Separate domains are outlined and can be represented with different patterns. (C) Some transmembrane polypeptides comprise sequences from similar sources. An example could be an Influenza Hemagglutinin gene. (D) Some transmembrane polypeptides may comprise sequences where signal peptides and extracellular domains from one source are combined with membrane spanning domains and cytoplasmic domains from other sources. (E) Some transmembrane polypeptides comprise sequences where each domain is from a different source. (F-G) Some transmembrane polypeptides comprise sequences in extracellular domains so that particles are targeted to phagocytes. Examples of this are not limited to extracellular domains comprising sequences similar to an antibody (F) or to a complement polypeptide (G) or a combination or fragment thereof. In the most preferred version of the current invention, transmembrane polypeptides comprise membrane spanning and cytoplasmic domains so that the sequences are complementary to core polypeptide lipid-binding domains.
[0011] FIG. 2 shows a legend of the schematics used in subsequent figures. The "transmembrane polypeptide LH" represents a transmembrane polypeptide of claim 5 that activates a fusogenic function when exposed to a low pH (LH) environment. The "low pH transmembrane polypeptide LH" represents a transmembrane polypeptide in a low pH environment. The "transmembrane polypeptide T" represents the transmembrane polypeptide from claim 5 comprising a sequence whereby the particle is targeted (T) to phagocytes. While the schematic represents separate polypeptides for fusogenic and targeting functions, these functions may be comprised in a single polypeptide. The "assembling core polypeptide" is a sequence comprising a function to assemble the core of the particle of claim 6. Maturation of particles are required for disassembly after or upon contacting the phagocyte. Domains of mature core polypeptides where domains have been separated by hydrolysis are represented by "hydrolytically matured core polypeptide" and "mature core polypeptide to be delivered." The "host antibody" is an antibody added to the particle before administration, or most preferably, by a subject's immune system after administration. The "phagocyte surface receptor" represents a receptor on the surface of the phagocyte that binds to transmembrane polypeptides, either directly or indirectly. The "inside phagocytic cell" represents the inside a phagocyte.
[0012] FIG. 3 shows a schematic of domains of transmembrane polypeptides and a proposed conformational change upon exposure to a low pH environment. (A) At least 2 functions of transmembrane polypeptides are claimed in the current version of the invention. One function is to target particles to phagocytes and another function is to fuse lipids of particles and phagocytes. Each function is schematically represented. Each transmembrane polypeptide comprises at least three domains, a membrane spanning domain, a cytoplasmic domain, and an extracellular domain. Membrane spanning domains are in contact with lipids and link extracellular domains to cytoplasmic domains. Cytoplasmic domains are inside of lipid-enveloped particles or contacts the cytoplasm of cells and are most preferred to complement the lipid-binding domain of core polypeptides. Signal peptides are not depicted in this schematic. Extracellular domains comprise sequences recognized by the subjects immune system, bound by antibodies, or bind directly to phagocyte surface receptors. Lipids are represented by a thickened black line extending across membrane spanning domains to represent contact between lipids and transmembrane polypeptides. (B-E) Transmembrane polypeptides T function in targeting particles to phagocytes. Panels B and C schematically represent transmembrane polypeptides T comprising sequences bound by antibodies. These sequences represent an indirect targeting to phagocytes whereby phagocyte surface receptors bind to antibodies bound to transmembrane polypeptides T of lipid-enveloped particles. Panels D and E schematically represent transmembrane polypeptides T comprising sequences binding directly to phagocyte surface receptors. A function of transmembrane polypeptides LH is to mediate mixing of lipids between particles and phagocytes. Mixing is mediated by conformational changes occurring upon exposure to a low-pH environment. The conformational changes occur whereby fusion peptides contact lipids of phagocytes. Contact disturbs equilibrium of lipid interactions whereby mixing between particle lipids and phagocyte lipids occur. This is represented in differences between the neutral pH conformation of transmembrane polypeptides LH represented in panels B and D versus the low pH conformation of transmembrane polypeptides LH represented in panels C and E. Current models of glycoprotein mediated fusion allows for hydrophobic peptide sequences to translocate from contacting lipids cis to the particle to contacting lipids trans to the particle.
[0013] FIG. 4 shows a schematic of 4 stages of delivery of polypeptides to be delivered by lipid-enveloped particles of claim 1. Lipids of producer cells, particles, and phagocytes are represented by boldened lines. The first stage (A) is an assembly of a plurality of least one of the core polypeptides of claim 4 and envelopment by a lipids comprising a plurality of least one of the transmembrane polypeptides of claim 5. This stage occurs in the cells of claim 3. Core polypeptides are matured by hydrolysis (particle maturation) so that the medium of the cell of claim 3 comprises lipid-enveloped particles of claim 1. (B) A mature lipid-enveloped particle of claim 1 is schematically represented. (C) Release of mature core polypeptides to be delivered into targeted cells involves exposure of lipid-enveloped particles to a low pH environment so that transmembrane polypeptides LH cause mixing of lipids from particles and target cells. After fusion of lipids, hydrolytically matured core polypeptides disassemble whereby mature core polypeptides to be delivered are released from particles. (D) Mature core polypeptides to be delivered are schematically represented inside a phagocyte. The preferred version of the current invention comprises mutations in polypeptides to be delivered so that the stability is altered. Increased stability is represented in (D) by a greater number of mature core polypeptides to be delivered compared to hydrolytically mature core polypeptide domains. Some applications may require destabilizing mutations.
[0014] FIG. 5 shows various states of lipid enveloped particles before fusion with phagocytes. (A) One version of the current invention uses antibodies to target a particle to phagocytes through opsonization. A lipid-enveloped particle coated with antibodies added to particles before administration or by the subject's immune system after administration is schematically represented. (B) A mature lipid-enveloped particle is represented as it exists in the medium of the cell of claim 3. This embodiment of the particle does not need to bind antibodies to target phagocytes. Transmembrane polypeptides T of this embodiment comprises sequences binding to phagocyte surface receptors. (C) A lipid-enveloped particle coated with antibodies is schematically represented binding to a phagocyte through contacts with phagocyte surface receptors. The schematic represents a version of the current invention whereby transmembrane polypeptides T comprise sequences so that phagocyte surface receptors bind particles indirectly. (D) Another version of the current invention is a particle comprising transmembrane polypeptides T comprising sequences similar to antibodies or Complement or a combination or fragment thereof so that phagocyte surface receptors bind directly to lipid-enveloped particles. Phagocyte surface receptors are schematically represented to bind directly to transmembrane polypeptides of particles of claim 1; and
[0015] FIG. 6 shows a schematic representation of particles binding directly and indirectly to a phagocyte and engulfment and exposure to a low pH environment whereby polypeptides to be delivered are released to phagocytes. (A) A lipid-enveloped particle is represented in 2 embodiments schematically separated by a line showing antibodies bound to transmembrane polypeptide T comprising sequences to which the host has been immunized on one side (marked "indirect") and transmembrane polypeptides T comprising antibody or complement domains on the other side (marked "direct"). Both direct and indirect binding are represented prior to contacting phagocytes. This representation occurs in all panels of this figure. (B) Binding to phagocyte surface receptors is schematically represented whereby engulfment of lipid-enveloped particles begins. (C) A lipid-enveloped particle is engulfed by a phagocyte and is represented to be enclosed in a compartment. Phagocytes acidify the compartment thereby activating the fusogenic function of transmembrane polypeptide LH. (D) An activated fusogenic function of transmembrane polypeptide LH causes mixing of particle lipids with phagocyte lipids. A result is release of mature core polypeptides to be delivered into the phagocyte. While a means of transmembrane polypeptides T binding to phagocytes can be different, the result is similar. Particles are moved to compartments of increasing acidity. Lowered pH activates enzymes that degrade the contents of the compartment. However, the invention allows escape of the polypeptides before degradation as transmembrane polypeptides LH mediate fusion of lipids between particles and phagocytes so that mature core polypeptides to be delivered are released.
DESCRIPTION
Definitions
[0016] The term lipids can include single molecules of lipids or groups of lipids organized into a monolayer or bilayer. The lipids are comprised by any embodiment of the particles of the present invention and by an organelle of producer and target cells. The lipids of the producer and target cells are not limited to the plasma membrane, Endoplasmic Reticulum, intermediate compartment, Golgi apparatus, trans-Golgi network, endosomes, lysosomes, phagosomes, and nuclear envelope.
[0017] The term polypeptide is used to mean a sequence of more than 2 amino acids. The term may include peptides that are generally considered to be sequences of less than about 100 amino acids and proteins that are generally considered to be sequences of greater than about 100 amino acids. These amino acid sequences are linked together to form polypeptides. Polypeptides are intended to include post-translational modifications, mutations, or sequences possessing >50% homology, or preferably >60% homology, or more preferably >70% homology, or most preferably >80% homology at the amino acid level to those defined by the nucleic acid sequences in this document.
[0018] Similar to the degeneracy of nucleic acid codons in specifying an amino acid, an amino acid sequence possesses degeneracy in specifying a structural conformation of polypeptides. It is the structure of the domain that specifies the function of the domain. Thus, domains are described by functions in the claims of this document, as many sequences of amino acids may achieve the claims of the assembled functional domains. While many naturally occurring sequences are included with this document, similar results could be achieved using polypeptide sequences designed de novo that specify structural requirements, and hence functional requirements, of the invention. Thus, the sequences comprised within this document are not a limitation of the invention, but merely a guide for assembly of functional domains to deliver polypeptides to phagocytes.
[0019] Polypeptide domains include sequences of amino acids comprising at least one function. A polypeptide may comprise more than one polypeptide domain. Polypeptide domains may have different origins linked together to make a single polypeptide. A single polypeptide domain may also make a polypeptide.
[0020] The term "fragment" is used to refer to a functional or structural domain of a polypeptide or protein. An example of a fragment is not limited to an Fc domain that is comprised by an antibody.
[0021] The term "polypeptide to be delivered" is used to refer to polypeptides encoded by the nucleic acids of claim 1 as a domain comprised within a core polypeptide whereby hydrolysis releases this domain from the core polypeptide so that it functions inside phagocytes. The domain may comprise transcription factors, antibodies, scaffolds for organelle biogenesis and polypeptide complexes, kinases, lipases, or other enzymes and mutants and fragments thereof. The domain may comprise nuclear factors and chromosome binding proteins. Polypeptides to be delivered may comprise chimeric polypeptide sequences whereby more than one polypeptide domain is linked to another. Polypeptides to be delivered may also comprise a vaccine antigen whereby the sequence is presented by phagocytes to lymphocytes and other cells so that the immune system can recognize the polypeptide comprising the sequences. The polypeptide to be delivered may also comprise a chimeric or de novo designed sequence.
[0022] The term "hydrolytic" is used to refer to hydrolysis of peptide bonds broken by chemical or enzymatic means. The term is used in this document to refer to the breaking of peptide bonds between amino acids of core polypeptides whereby domains of core polypeptides are released to allow disassembly of particles and release of polypeptides to be delivered upon contacting the phagocyte.
[0023] The term fusion peptide refers to a peptide sequence comprising hydrophobic amino acids whereby the peptide has a high affinity for contacting lipids. The fusion peptide contacts lipids and causes disruption of equilibrium between lipids. The fusion peptide may be comprised within a polypeptide sequence. Hydrophobic amino acids are leucine, isoleucine, and valine.
[0024] The terms fusogenic and fusion refers to mixing of lipids. In the context of this document, the term refers to transmembrane polypeptides LH comprising a fusion peptide in the extracellular domain and a membrane spanning domain. Exposure to an acidic environment causes conformational changes in extracellular domains of transmembrane polypeptides LH whereby fusion peptides insert into lipids of phagocytes. The membrane spanning domain of transmembrane polypeptides LH contacts lipids of the particle. The linkage of the lipids of the particle to the disrupted lipid equilibrium on the phagocyte causes mixing of the lipids.
[0025] A production cell comprises the nucleic acids of claim 1 operably linked to expression control sequences so that core polypeptides and transmembrane polypeptides are expressed. Production cells can derive from bacteria, yeast, insect, fish, avian, or mammalian origins. Production cells generally culture in a medium supporting growth of the cells while lipid-enveloped particles are produced and collected from the medium.
[0026] The target cell is a cell in a mixed population for which particles have higher affinity compared to other cells. Target cells are those having high capacity for receptor-mediated phagocytosis. Target cells are most preferred to be phagocytes in a human or other organism or subject. Target cells may also be cultured in vitro.
[0027] Phagocytes are defined as cells having a high propensity to engulf lipid-enveloped particles. These cells are not limited to dendritic cells, macrophages, neutrophils, and granulocytes and the subtypes of these cells.
[0028] The term "immune recognition" is defined as a specific reaction by the host immune system to bind to molecules. In the context of this document, the molecules are any polypeptides included on particles, either directly or indirectly. Immune recognition is mediated by antibodies or a major-histocompatibility complex.
[0029] Opsonization is the alteration of surfaces of particles making the particles more easily engulfed by phagocytes. Alterations comprise binding of particles by antibodies and complement proteins. Coating particles with antibodies prior to administering particles and transmembrane polypeptides comprising antibody domains or complement domains may functionally mimic opsonization so that particles are engulfed by phagocytes.
[0030] Surface receptors are polypeptides in contact with phagocytes. Surface receptors may be encoded by the phagocyte. The receptors are in contact with a phagocyte through indirect and direct interactions and may comprise one or more membrane spanning domains.
[0031] A subject is any organism, patient, or host possessing an immune system whereby adaptive and innate immunity cooperate to remove antigens.
Overview
[0032] The isolated nucleic acids claimed comprise sequences so that when operably linked to an expression regulatory element, such as commonly used CMV or SV40 promoters or constitutively active yeast or bacterial promoters, and transfected into cells, encoded polypeptides are expressed. Cells that express the nucleic acids become known as "producer cells." Producer cells can be any type of cell, but some cell types are preferred. Among the more preferred cell types for producer cells are 293T, Jurkat, Chinese Hamster Ovary, and yeast cells. These cells are known to someone of ordinary skill in the science. The producer cells express the nucleic acids transiently after transfection. More preferably, stably transfected cells are selected and propagated so that the progeny cells continue to express the nucleic acids.
[0033] Encoded polypeptides comprise domains so that polypeptides assemble into particles that are enveloped by lipids of the producer cells. At least two categories of polypeptides, core polypeptides and transmembrane polypeptides, cooperate to form particles.
[0034] One polypeptide category comprises core polypeptides. Core polypeptides may comprise at least one lipid-binding domain so that polypeptides contact lipids of producer cells. Lipid-binding domains may include several features, such as covalently linked lipids and structural folds comprising a surface of basic amino acids that contact lipids.
[0035] At least one of the encoded core polypeptides may comprise at least one interaction domain so that a plurality of core polypeptides bind to each other. A plurality of interaction domains binding in trans to interaction domains comprised within other core polypeptides causes oligomerization of core polypeptides whereby an assembly of 500 to 10,000 core polypeptides is formed.
[0036] Lipid-binding and interaction domains allow core polypeptides to assemble into particles that are enveloped by lipids. Lipid-enveloped particles may be extruded from producer cells by the described oligomerization and lipid-binding events depending on the producer cell type, or may include at least one late domain so that extrusion occurs. A late domain may comprise at least one polypeptide sequence whereby a ubiquitin molecule is attached to facilitate release from producer cells.
[0037] Domains function to assemble core polypeptides into lipid-enveloped particles that are released from producer cells. Other domains may be included in core polypeptides so that core polypeptides disassemble after lipids of particles and phagocytes fuse. Core polypeptides may comprise protease domains that hydrolyzes peptide bonds between specific sequences of amino acids. A plurality of these sequences hydrolyzed by a protease or chemical application may be encoded within core polypeptides whereby core polypeptides are hydrolyzed. A hydrolytic process whereby the core polypeptide is prepared for disassembly is called particle maturation (FIG. 4A and FIG. 4B).
[0038] Particle maturation occurs so that core polypeptide domains can disassemble and be released to function in target cells. Core polypeptides comprise another domain whereby this domain functions at target cells. This domain comprises a polypeptide to be delivered as also described in FIG. 1. Polypeptides to be delivered comprise, but are not limited to, transcription factors, antibodies, scaffolds, antigens to function as vaccines, and chimeric and designed and engineered polypeptide sequences. Polypeptides to be delivered may also comprise fragments and mutations and post-translational modifications and mimics of post-translational modifications of the polypeptide sequences mentioned above.
[0039] Particles exclude nucleic acids unless required for the application. The exclusion of nucleic acids or the incorporation of specific nucleic acids may be quantified using polymerase chain reaction with degenerate or specific oligonucleotides. Specific nucleic acid sequences may be incorporated into particles by a polypeptide to be delivered that includes specific binding affinity for the desired sequences.
[0040] It is preferred that polypeptides to be delivered comprise mutations altering stability and half-life and activity of the polypeptides in target cells relative to naturally occurring domains with similar sequences. For example, if a transcription factor is phosphorylated at a particular serine residue by a kinase to promote ubiquitination and proteosomal degradation, then this serine residue could be mutated whereby phosphorylation does not occur and the function of the transcription factor is prolonged. Another example is a mutation of a kinase whereby the kinase activity is constitutively activated.
[0041] Another polypeptide category are transmembrane polypeptides. Transmembrane polypeptides comprise at least one signal peptide domain so that nascent polypeptide chains are cotranslationally translocated to the endoplasmic reticulum of producer cells. Signal peptide domains are linked to extracellular domains whereby extracellular domains contact the extracellular medium.
[0042] Transmembrane polypeptides may also comprise at least one cytoplasmic domain so that extracellular domains are anchored to lipid envelopes. Cytoplasmic domains are located on the cytoplasmic side of lipid envelopes. Transmembrane polypeptides may also comprise at least one membrane spanning domain so that cytoplasmic domains and extracellular domains of a transmembrane polypeptide are linked.
[0043] Versions of this invention use lipid-enveloped particles comprising a plurality of 2 transmembrane polypeptides to target to and fuse to phagocytes. The transmembrane polypeptides are designated transmembrane polypeptide T (for Targeting) and transmembrane polypeptide LH (for low pH). Different categories of transmembrane polypeptides may comprise the same sequences.
[0044] Transmembrane polypeptide LH comprises an extracellular domain whereby structural conformations of the polypeptide changes upon exposure to a low pH environment. The conformational change of transmembrane polypeptide LH allows lipids of particles to fuse with lipids of target cells. Fusion of particle and phagocyte lipids occurs so that mature core polypeptide domains are delivered to target cells.
[0045] Another function of transmembrane polypeptides of the particle is targeting particles to cells whereby the cell type particles contact is specified. As described in FIG. 3, transmembrane polypeptide T may function directly or indirectly.
[0046] In one version of the current invention nucleic acids encode an extracellular domain of transmembrane polypeptides T comprising sequences similar to complement 3 or a fragment thereof, such as complement 3b or 3a whereby binding of polypeptides comprising the sequence of complement 3 or a fragment thereof to cell surface receptors causing engulfment of particles.
[0047] In another version of the current invention nucleic acids encode an extracellular domain of transmembrane polypeptides T comprising sequences similar to polypeptide sequences of Influenza Hemagglutinin to which the subject has been vaccinated. This hemagglutinin sequence may have been used in a current vaccine formulation or a vaccine formulation from a prior year. The sequence may also comprise part of a vaccination regimen. Upon administering the particle to a subject, hemagglutinin sequences are opsonized.
[0048] Examples of hemagglutinin sequences include, but are not limited to H1 as in SEQ ID NO: 001, H2 as in SEQ ID NO: 002, H3 as in SEQ ID NO: 003, H4 as in SEQ ID NO: 004, H5 as in SEQ ID NO: 005, H6 as in SEQ ID NO: 006, H7 as in SEQ ID NO: 007, H8 as in SEQ ID NO: 008, H9 as in SEQ ID NO: 009, H10 as in SEQ ID NO: 010, H11 as in SEQ ID NO: 011, H12 as in SEQ ID NO: 012, H13 as in SEQ ID NO: 013, H14 as in SEQ ID NO: 014, H15 as in SEQ ID NO: 015, and H16 as in SEQ ID NO: 016 from mammalian and avian sources. Examples of sequences are not limited to members of the Influenza A and Influenza B families as in SEQ ID NO: 017.
[0049] Each hemagglutinin molecule forms an oligomeric structure of 3 molecules. Each of these molecules has 2 binding sites for sialic acid. For Influenza, sialic acid acts as the cell surface receptor and because sialic acid is a common conjugate attached to molecules, the surface receptor for Influenza is on many cell types. The nucleic acids encoding transmembrane polypeptides comprising hemagglutinin sequences would most preferably comprise mutations so that binding to sialic acid is reduced. Reduction in sialic acid binding is such that the claimed indirect or direct means of targeting to phagocytes as described in FIG. 3, FIG. 5, and FIG. 6 are the dominant mode of targeting.
[0050] Membrane spanning and cytoplasmic domains of transmembrane polypeptides of the particle may comprise sequences encoding membrane spanning and cytoplasmic domains from the Influenza Hemagglutinin. Membrane spanning and cytoplasmic domains of transmembrane polypeptides may comprise sequences encoding domains that are complementary to lipid-binding domain of core polypeptides. Membrane spanning and cytoplasmic domains of transmembrane polypeptides comprise sequences encoding other transmembrane proteins as one skilled in the science would readily be able to define.
[0051] In each of these versions of the inventions described, the transmembrane polypeptide T comprises sequences whereby the particle is targeted to phagocytes by an indirect or direct binding to phagocyte surface receptors and engulfed by a phagocyte. Acidification of engulfed compartments occur whereby transmembrane polypeptides LH are conformationally changed whereby fusion of lipids release mature polypeptides to be delivered to the phagocyte.
[0052] A lipid-enveloped particle is assembled when a plurality of at least one transmembrane polypeptide is combined with a plurality of at least one core polypeptide to form an oligomeric assembly whereby the assembly is enveloped with lipids from producer cells and extruded into medium. Particles may comprise about 500 to 10,000 core polypeptides and about 100 to 5,000 transmembrane polypeptides. Some particles may comprise greater than about 10,000 core polypeptides and greater than about 5,000 transmembrane polypeptides.
Detailed Description of the Elements
[0053] The structure of the invention allows for more than one embodiment of particles to be produced. The following description is just one example of elements operable comprised by the invention.
[0054] To begin using the inventions described herein, particles must be assembled in producer cells by expressing the nucleic acids of claim 1. Particles are assembled by expressing nucleic acids in producer cells as in claim 3. Producer cells are cultured as one of average skill in the science would easily understand. Producer cells are most commonly 293T cells when culturing producer cells in volumes less than about 5 liters. It is preferred that non-adherent producer cells be used in volumes greater than about 3 liters. Examples of non-adherent producer cells are not limited to CHO, NS/0, BHK, and 293. New cells are being developed that have desirable qualities for manufacturing volumes greater than about 3 liters and are available commercially and through license. These cells may also be transfected with the nucleic acids of claim 2 and stable transfectants generated to express the nucleic acids of claim 1 as one skilled in the science would understand. Most preferred characteristics for producer cell lines are rapidly dividing cells that can grow to at least about 20,000,000 cells per milliliter, have a capacity to produce at least about 8 picograms of secreted particles per cell per day production, are capable of continued passage under common eukaryotic cell culture conditions, and whereby the particles of claim 1 comprise greater than about 80% of the polypeptides secreted into the medium. Cells having all of these characteristics are most preferred. If production of particles at lower efficiencies can be tolerated for an application, then having all of these characteristics is not required.
[0055] The nucleic acid sequences encoding the polypeptides of claim 1 may vary depending on the need of the user and includes degenerate variants of the sequences included in this invention. The sequences can originate from any source so that when they are combined lipid-enveloped particles are assembled that deliver polypeptides to be delivered to phagocytes.
[0056] The codon usage of the nucleic acids encoding the polypeptides should be optimized for the species of the producer cell type. For example, if 293T cells are chosen as producer cells, then the nucleic acids of claim 1 should encode polypeptides using optimized codons for humans. Further, if CHO cells are chosen as producer cells, then the nucleic acids of claim 1 should encode polypeptides using optimized codons for hamsters.
[0057] The nucleic acids of claim 1 are placed into vector and operably linked to an expression control sequence, such as a CMV or SV40 promoter, and transfected into the producer cells through lipid-transfection, chemical precipitation, electroporation, or other commercially available means. The producer cells may comprise the nucleic acids transiently or, more preferably, stable transfectants selected and cloned as someone skilled in the science would easily understand. The molar ratio of nucleic acids encoding core polypeptides to nucleic acids encoding transmembrane polypeptides is typically at least about 1:1 and no more than 20:1 and at least about 1:20. If more than one sequence of transmembrane polypeptide or core polypeptide is used then the ratio should include the sum of each sequence in each category. For example, an application that requires 2 transmembrane polypeptides and 1 core polypeptide might use about 0.25 parts of each transmembrane polypeptide and about 0.50 parts of the core polypeptide.
[0058] The producer cells of claim 3 express core polypeptides and transmembrane polypeptides of claim 4 and claim 5 so that the polypeptides assemble into particles enveloped by lipids of producer cells. Particles are purified from the medium to a degree as needed for the application. For some applications the medium comprising particles is sufficient without further isolation. Purification and concentration of particles are achieved by centrifugation and chromatography as one skilled in the science would understand.
[0059] Particles can be quantified by counting particles per volume, spectrophotometric analysis, lipid mass measurement, or by SDS-PAGE analysis of polypeptides all of which are easily understood by someone skilled in the science.
Application and Formulation
[0060] Particles can be administered to a subject as a therapy in several ways. Particles may be applied through rectal or vaginal suppository, topically, directly to a wound or abrasion, orally, subcutaneously, intravascularly, intramuscularly, and inhaled. A formulation may be one allowed by current technology and maintains the pH of particles at no less than about 7. Particles can be incorporated into a salve, lotion, paste, cream, suspension, solution, salt, powder, gel, inhalant, suppository, or capsule administered to a subject topically, inhaled, injected, by drops, or swallowed as needed for the application or therapy.
[0061] Before administration, it is critical that pH be maintained above that required to induce conformational changes to cause fusion. This pH may vary according to the transmembrane polypeptide sequence used, but conformational changes are usually induced at about pH5.5.
[0062] The current invention provides for several embodiments for targeting through transmembrane polypeptide T and fusion through transmembrane polypeptide LH. A therapy regimen may include different embodiments or particles comprising different transmembrane polypeptides T and transmembrane polypeptides LH as needed to maintain efficacy of delivery.
[0063] Samples of blood may be collected from the subject during therapy so that the degree of efficacy of delivery can be determined. This is performed by treating a small amount of the particles (an amount sufficient to deliver polypeptides to about 1,000,000 cells) with dilutions of the subject's blood. The precise amounts of particles and blood used are not important as long as a relative measurement is made with particles capable of delivering polypeptides to a target cells but not exposed to the subject's blood.
[0064] It is expected that the subject's blood will increase the amount of polypeptide delivered to phagocytes when the efficacy of delivery is through immune recognition of transmembrane polypeptides by the host.
[0065] Treating the particles with the subject's blood might also result in neutralization of the transmembrane polypeptide LH. If a reduction in efficacy of delivery results from the presence of the subject's blood then the embodiment of transmembrane polypeptide LH administered to the host should be substituted with another embodiment of transmembrane polypeptide LH having greater efficacy of delivery than the administered embodiment.
[0066] Efficacy of delivery is measured by determining percent change of polypeptides to be delivered entering phagocytes from that which is administered to cells. For example, 10,000 picograms of particles are administered to 1,000,000 phagocytes whereby 500,000 phagocytes exhibit the desired change. If the subjects blood comprises antibodies to the particle, then 70% of phagocytes might exhibit the desired change. Measurements are made using microscopy or biochemistry as allowed by the polypeptide to be delivered. The subject's blood may be tested with various embodiments of the transmembrane polypeptides to determine the optimal transmembrane polypeptides.
EXAMPLES
Example 1
[0067] This prospective example demonstrates using particles for a vaccine against HIV, Bacillus anthracis, and Poxviridae.
[0068] Producer cells of claim 3 are transfected to express about 0.5 to 0.0035 picomoles per 1,000,000 cells of each of two classes of transmembrane polypeptides and two classes of core polypeptides. Transmembrane polypeptides T comprise sequences similar to immunoglobin epsilon constant region similar to SEQ ID NO: 018. This version of the transmembrane polypeptide T comprises a targeting function that binds to Fc receptors on the surface of phagocytes inducing engulfment. Transmembrane polypeptides LH comprise sequences similar to H1 Hemagglutinin from H1 N1 Influenza A/California/7/2009 with mutations reducing affinity for sialic acid similar to SEQ ID NO: 019. This version of the transmembrane polypeptide LH comprises a target function through indirect binding of antibodies produced in subjects receiving the 2010 and 2011 Influenza vaccines and a fusogenic function through a low pH conformational change intrinsic to Influenza Hemagglutinins. One of the core polypeptides comprises lipid-binding, interaction, and late domains with a protease domain similar to SEQ ID NO: 020. Another core polypeptide comprises one sequence also comprising lipid-binding, interaction, and late domains with a protein to be delivered comprising a sequence from HIV-1, an anthrax epitope, and a smallpox epitope fused to a proteosomal targeting sequence similar to SEQ ID NO: 021.
[0069] Medium from cells expressing the nucleic acids comprise assembled particles. The particles are isolated by centrifugation or chromatography as one skilled in the science would understand.
[0070] Particles are treated with a pharmaceutically effective amount of lipopolysaccharide, or similar compound, whereby the molecule activates toll-like receptors in phagocytes upon contacting particles. Activation of toll-like receptors in the phagocytes promote presentation of antigens to the immune system.
[0071] Isolated particles can be quantified by counting particles per volume, spectrophotometric analysis, lipid mass measurement, SDS-PAGE analysis of polypeptides, or by functional analysis, all of which are easily understood by someone skilled in the science.
[0072] A pharmaceutically effective amount of particles are introduced into the host by rectal or vaginal suppository or inhaled using a pharmaceutically acceptable carrier or diluent formulation. Resident phagocytes along the epithelium recognize the complement 3b sequences of the particle's transmembrane polypeptide T and phagocytose the particles. Upon acidification of the phagosome, transmembrane polypeptides LH undergo conformational changes whereby the lipids of the particle and the phagosome fuse to release the contents of the particle into the phagocyte. A mass of about 100 particles should comprise a number of mature polypeptides to be delivered sufficient for a phagocyte to present the antigenic epitopes, but may be as low one particle.
[0073] A vaccination is further implemented by polypeptides to be delivered comprising an HIV sequence along with a proteosome targeting sequence so that the polypeptides to be delivered are hydrolyzed for antigen presentation by the proteosome for binding to the major histocompatibility complexes (MHC). Antigen presentation is also implemented by including lipopolysaccharide or similar compound in the particle lipids whereby the signaling pathway initiated by toll-like receptors are activated.
[0074] Transmembrane polypeptides may also comprise an HIV sequence in the extracellular domain whereby after repeated applications, antibodies can be developed by the host to the polypeptide sequence. This utilization of the invention would allow for vaccinations to be incorporated. Immunization would occur on an optimal schedule.
Example 2
[0075] This prospective example demonstrates using particles to deliver peroxisome proliferator-activated receptor (PPAR) and liver X nuclear receptor (LXR) transcription factors whereby phagocytes change from having M1 characteristics to having M2 characteristics (Journal of Clinical Investigation, (2007) 117:89-93 and references therein).
[0076] Producer cells of claim 3 are transfected to express about 0.5 to 0.0035 picomoles per 1,000,000 cells or stably transfected and selected to express each of two classes of transmembrane polypeptides and two classes of core polypeptides. Transmembrane polypeptides T comprise a sequences similar to Fc fragments of immunoglobins similar to SEQ ID NO: 022. Transmembrane polypeptides LH comprise sequences similar to H3 Hemagglutinin from H3N2 Influenza A/Perth/16/2009 (H3N2) with mutations reducing affinity for sialic acid similar to SEQ ID NO: 023. This embodiment of the transmembrane polypeptide LH comprises targeting functions through indirect binding of antibodies produced in subjects receiving the 2011/2012 Influenza vaccines and a fusogenic functions through low pH conformational changes intrinsic to Influenza Hemagglutinins. Core polypeptides comprise lipid-binding, interaction, and late domains similar to SEQ ID NO: 024. One of the core polypeptides further comprises a protease domain similar to SEQ ID NO: 025. Another of the core polypeptides further comprises a protein to be delivered comprising sequences similar to PPAR or LXR similar to SEQ ID NO: 026 and SEQ ID NO: 027.
[0077] Medium from cells expressing the nucleic acids comprise particles. The particles are isolated by centrifugation and chromatography as one skilled in the science would understand.
[0078] Isolated particles can be quantified by counting particles per unit volume, spectrophotometric analysis, lipid mass measurement, SDS-PAGE analysis of polypeptides, or by functional qualification, all of which are easily understood by someone skilled in the science. It is expected that about 100 particles will be required to change a phagocyte from characteristics of M1 to characteristics of M2 and may be as low as 1 particle. Doses given to an organism are determined by the number of phagocytes desired to be changed and pharmaceutically optimized for the application.
[0079] Particles may be administered using a transdermal device, subcutaneously, and intravascularly using a pharmaceutically acceptable carrier and diluent formulation to a subject where phagocytes bind directly to the Fc polypeptide sequence on the transmembrane polypeptide T of the particle and indirectly through antibodies bound to the transmembrane polypeptide LH. Subjects administered particles would have all of the benefits afforded by a phagocyte having M2 characteristics. Examples of these benefits are not limited to reduction of an atherosclerotic plaque and addition of extracellular matrix to assist in tissue regeneration. Particles may also be applied topically to a wound or abrasion to promote healing.
[0080] In another embodiment of this invention core polypeptides include sequences comprising lipid-binding, interaction, and late domains with a protein to be delivered comprising a sequence similar to oxidosqualene cyclase similar to SEQ ID NO: 028. These particles could also be used to treat subjects with atherosclerosis or metabolic diseases.
Example 3
[0081] This prospective example demonstrates using particles to deliver PPAR transcription factors to patients with liver disease and cirrhosis whereby hepatic phagocytes catabolize lipids.
[0082] Producer cells of claim 3 transfected to express about 0.5 to 0.0035 picomoles per 1,000,000 cells of each of two classes of transmembrane polypeptides and two classes of core polypeptides. The transmembrane polypeptide T comprises a sequence encoding a sequence similar to a complement 3b domain similar to SEQ ID NO: 029. Transmembrane polypeptides LH comprise sequences encoding the H5 Hemagglutinin from H5N1 Influenza A with mutations reducing affinity for sialic acid similar to SEQ ID NO: 030. This version of the transmembrane polypeptide LH comprises functions to vaccinate the patient to H5 Influenza Hemagglutinin and a fusogenic function through the low pH conformational changes of the polypeptides. In this embodiment of the current invention, the first doses to a subject are expected to be less efficacious than subsequent doses as the subject develops antibodies to the polypeptides. In another embodiment, antibodies from another source could be used to coat the particles before administration and the dosing regimens can be changed to a regimen optimally designed for the application. Core polypeptides comprise lipid-binding, interaction, and late domains similar to SEQ ID NO: 031. One of the core polypeptides further comprises a protease domain similar to SEQ ID NO: 032. Another of the core polypeptides further comprises a protein to be delivered comprising a sequence similar to PPAR as in SEQ ID NO: 033.
[0083] Medium from the cells expressing the nucleic acids of claim 1 comprise particles. Particles are isolated by centrifugation and chromatography as one skilled in the science would understand.
[0084] Isolated particles can be quantified by counting particles per unit volume, spectrophotometric analysis, lipid mass measurement, SDS-PAGE analysis of polypeptides, or by a functional assay, all of which are easily understood by someone skilled in the science. It is expected that less than about 100 particles will be required to change a phagocyte from characteristics of M1 to characteristics of an M2 and may be as low as 1 particle. Doses given to an organism would be determined by the number of phagocytes desired to be changed and pharmaceutically optimized.
[0085] Particles may be administered using a transdermal device, subcutaneously, intravascularly, and through a pharmaceutically acceptable carrier or diluent formulation to an organism where phagocytes bind indirectly through antibodies bound to transmembrane polypeptides LH or directly to complement 3b domains of transmembrane polypeptides T. Subjects administered particles would have all of the benefits afforded by phagocytes having increased catabolism of lipids. Examples of these benefits are not limited to reduction of fatty acids accumulated in the liver due to Hepatitis infections, drug abuse, or hereditary liver disease.
Example 4
[0086] This prospective example demonstrates a kit sold so that the user may deliver polypeptides to cells as needed. The nucleic acids of claim 1 are made available as a kit whereby the end user would ligate a nucleic acid sequence encoding a polypeptide domain of interest into the nucleic acid sequence of the polypeptide to be delivered domain whereby the domain is incorporated into particles. The nucleic acids would be placed into expression vectors so that the nucleic acids of claim 1 are operably linked to an expression control sequence. The kit could include at least 1 transmembrane polypeptide and at least 1 core polypeptide. Nucleic acids encoding core polypeptides comprise sequences encoding the lipid-binding, interaction, and late domains. Nucleic acids encoding core polypeptides comprising a protease domain are also included. Nucleic acids encoding core polypeptides also comprising multi-cloning sites or sites where nucleic acids could be included by someone of ordinary skill in the science. The kit could also include a cell line of claim 3 stably expressing one or more of the nucleic acids of claim 1 operably linked to expression control sequences. The kit could also include a cell line to transfect with the nucleic acids of claim 1 comprised in an expression vector and operably linked to expression control sequences. The kit could include all of the components necessary to generate lipid-enveloped particles comprising mature polypeptides to be delivered.
How the Invention is Used
[0087] In one embodiment of the current invention the nucleic acids are grouped and sold as a kit. The kit includes a cell line of type that is preferred as a producer cell line. The instructions with the kit explain the preferred methods for optimizing the production of particles and how to apply the particles. The kit allows choice of how to use the invention for therapies and experiments.
[0088] In another embodiment of the current invention the particles are generated and sold as a pharmaceutical. In this embodiment particles are generated with the desired polypeptide to be delivered domain and the isolated mature particles are included in a pharmaceutically acceptable carrier or diluent formulation.
[0089] The amount of particle to be administered and the dosing regimen may vary depending on such factors as desired biological endpoints, routes of administration, target tissues, and severity of the diseases. These factors will be appreciated by those skilled in the science and further developed as production and administration to humans is initiated.
[0090] The reaction of the subject's blood to the administered particles should be experimentally determined periodically between and during doses.
Advantages of The Invention
[0091] The present invention described herein has many advantages, including targeting lipid enveloped particles to phagocytes with specificity not previously achieved. A limitation of gene therapy has been neutralization of vectors by a subject's immune system. This immune recognition has also caused painful adverse reactions by the subject, sometimes resulting in death. Unintended effects of gene therapy have been inadvertently amplified by increasing amounts of vector in given doses to increase the likelihood of contacting target cells.
[0092] Another advantage of the present invention is a therapy administered in very low doses due to exquisite precision of the immune system in recognition and engulfment of particles and antigens. The present invention uses a transmembrane polypeptide recognized as antigen by phagocytes to mediate this engulfment and a transmembrane polypeptide that fuses lipids of phagocytes with particles. The fusion of lipids results in mixing of contents of particles and phagocytes. The structures of the particles result in a process used as a therapeutic for diseases and as a research product to change the nature of phagocytes, whose role in overcoming disease pathologies is becoming better understood.
[0093] Particles are also assembled so that, when desired, nucleic acids are excluded from particles. This provides an advantage in limited "side effects" and unintended, potentially dangerous effects when used in a therapy.
[0094] These advantages are not a comprehensive description of all of the advantages of the invention, nor are these advantages required in all versions of the invention.
Alternatives
[0095] Although the present invention has been described in considerable detail with reference to certain preferred versions thereof, other versions are possible. For example, the concepts and functionality of the domains described for core polypeptides and transmembrane polypeptides could be achieved by de novo design of a polypeptide sequence that could not be predicted here. As degeneracy of the genetic code allows multiple nucleic acid triplets to encode single amino acids, multiple amino acids could be linked into variations of polypeptides encoding single domains. Thus, degeneracy also exists in the folds of domains encoded by amino acids. Therefore, the spirit and scope of the appended claims should not be limited to the description of the preferred versions comprised herein.
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Sequence CWU
1
1
3311701DNAInfluenza A virus 1atggaagcaa aactactcgt attattctgc atgttcgctg
tgctaaaagc cgacaccatc 60tgtataggct atcatgcaaa caactctaca gacactgtcg
acacagtgct agaaaagaat 120gtaaccgtga ctcactcagt taatttgctc gaagacaacc
ataatggaaa actctgcaag 180ctgaacggga tagccccatt acaactagga aaatgcaacg
tagcggggtg gctcctcggc 240aatccggagt gtgacctgct gctcactgcg aattcatggt
cctatataat agaaacttca 300aattcagaaa atggaacgtg ctaccccggg gaattcattg
attatgaaga attgcgagaa 360aaactaagtt cagtgtcttc atttgagaaa tttgagattt
tcccgaaggc aagctcgtgg 420ccaaatcatg agacaaccaa aggtgtcaca gctgcatgct
cttactctgg agctagcagt 480ttttatcgaa atttgctgtg gataacaaag aagggaaatt
cctatcctaa actcagtaaa 540tcatacacga acaacaaggg aaaagaagta cttgtactct
ggggagtgca tcaccctcca 600actacaaatg aacaacagac cctctatcag aatactggcg
catatgtctc agtaggatca 660tcaaagtata accggaggtt cacacctgaa atagcggcca
gacctaaagt cagagggcaa 720gctggtagga tgaactatta ttggacacta ttggatcaag
gagacacaat aacatttgaa 780gcaactggga acttaatagc accatggtat gcttttgcac
taaataaggg ctctgattct 840ggtattataa catcagatgc tccggttcat gattgtgaca
caaagtgcca aacacctcat 900ggtgccatta acagtagtct ccctttccag aacgtgcatc
ctatcactat tggagaatgc 960cctaaatatg ttaaaagcac caaactaagg atggcaacag
gcctgagaaa cattccttcc 1020gttcaatcca gaggactctt tggagcaatt gctggattca
ttgaaggagg atggactgga 1080atgatagatg ggtggtatgg gtatcatcat cagaatgagc
aaggttctgg ttatgcagct 1140gatcagaaga gcacacaaaa tgcgatcgat ggaataacca
acaaagtgaa ctcagtaatt 1200gagaaaatga acactcaatt cactgcagtg ggtaaggagt
tcaacaatct ggagagaaga 1260attgagaatc tgaataaaaa agttgacgat gggtttctgg
acatttggac gtacaatgca 1320gaattgctcg ttttgctcga gaatgaaagg accttggatt
tccatgactc caatgtgagg 1380aatctgtatg aaaaggtcaa atcacaattg aggaataatg
ccaaagaaat cgggaacggg 1440tgcttcgagt tctatcacaa atgtgatgac gagtgcatgg
agagtgtgaa aaacggcaca 1500tatgactatc ccaagtactc agaggagtcc aaactaaaca
gagaagagat agacggggta 1560aaattggaat caatgggggt ttaccagatt ttggcgatct
actccacagt cgccagttcc 1620ctggtcttgt tagtctccct gggggcaatc agtttctgga
tgtgttctaa tgggtcattg 1680caatgcagaa tatgcattta g
170121773DNAInfluenza A virus 2agcaaaagca
ggggttatac catagacaat caaagcaaag acaatggcca tcatttatct 60aatccttctg
ttcacagcag tgagagggga ccagatatgc gttgggtacc attccaacaa 120ttccacagaa
aaggttgaca caattctaga gagaaatgtc actgtgactc acgctcagga 180cattcttgag
aagactcaca atggaaagtt atgcaaactg aacggaatcc ctccacttga 240attaggggat
tgcagcattg ccggatggct ccttggaaat ccagaatgtg atagacttct 300aactgtgcca
gaatggtcat atataatgga gaaagaaaat ccaaggaatg gtttgtgcta 360cccaggcagt
ttcaatgatt atgaagaatt gaaacatctt ctcagcagag tgacacattt 420cgagaaagta
aagattctgc ccaaagatag gtggacacag catacaacaa ctggaggttc 480acgggcttgc
gcagtatctg gtaatccatc attcttcagg aacatggtct ggttgacaaa 540gaaaggatcg
aattatccag ttgccaaagg atcatacaac aatacaagtg gagaacaaat 600gctgatcatt
tggggagtac accaccccaa tgatgaaact gaacaaagaa cattgtatca 660gaatgtgggg
acctatgtgt cagtaggaac atcaacattg aataaaaggt cactcccaga 720aatagcaaca
agacctaaag tgaatggaca aggaggtaga atggaattct cgtggactat 780cttagatata
tgggacacca taaatttcga gagcactggt aatctaattg caccagaata 840tggtttcaaa
atatccaaac gaggtagttc agggatcatg aaaacagaag gaacacttga 900aaactgcgag
accaagtgcc aaagtccttt gggagcaata aatacaacgt tgccctttca 960caatatccac
ccactgacca ttggtgagtg ccccaaatat gtaaaatcgg aaagattagt 1020cttagcaaca
ggactaagaa acgtccctca gattgaatca aggggattgt ttggggcaat 1080agctggtttt
atagaggggg gatggcaagg aatggttgat ggttggtatg ggtaccatca 1140cagcaacgac
cagggatccg ggtatgcagc agacaaagaa tccactcaaa aggcaattga 1200tggaatcacc
aacaaggtaa attctgtgat tgaaaagatg aacacccaat tcgaagctgt 1260tggaaaagaa
ttcagtaact tggagaaaag actggagaac ttgaataaaa agatggagga 1320cggatttcta
ggtgtgtgga catacaatgc cgagctcctg gttctaatgg aaaatgagag 1380gacacttgac
tttcatgatt ctaatgtcaa gaatctatat gataaagtca gaatgcaact 1440gagggacaat
gcgaaagagc tagggaatgg atgttttgaa ttttatcaca aatgtgatga 1500tgaatgtatg
aacagtgtga agaatgggac atatgattat cccaagtatg aagaggagtc 1560taaactaaac
aggaatgaaa tcaaaggggt aaaattgagc aatatggggg tttatcaaat 1620ccttgccatc
tatgctacag tagcaggttc cctgtcactg gcaatcatga tagctgggat 1680ctctttatgg
atgtgctcca acgggtctct gcaatgcaga atctgcatat gattatcagt 1740cattttataa
ttaaaaacac ccttgtttct act
177331731DNAInfluenza A virus 3taattctatt aaccatgaag actatcattg
ctttgagcca cattttatgt ctggttttcg 60ctcaaaaact tcccggaaat gacaacagca
cagcaacgct atgcctggga catcatgcag 120tgccaaacgg aacgctagtg aaaacaatca
cgaatgatca aattgaagtg actaatgcta 180ctgagttggt tcagagttct tcaacaggta
gaatatgcga cagtcctcac cgaatccttg 240atggaaaaaa ctgcacactg atagatgctc
tattgggaga ccctcattgt gatggcttcc 300aaaataagga atgggacctt tttgttgaac
gcagcaaagc ttacagcaac tgttaccctt 360atgatgtgcc ggattatgcc tcccttaggt
cactagttgc ctcatcaggc accctggaat 420ttatcaatga agacttcaat tggactggag
tcgctcagga tgggggaagc tatgcttgca 480aaaggggatc tgttaacagt ttctttagta
gattgaattg gttgcacaaa ttagaataca 540aatatccagc gctgaacgtg actatgccaa
acaatggcaa atttgacaaa ttgtacattt 600ggggggttca ccacccgagc acggacagtg
accaaaccag cctatatgtt cgagcatcag 660ggagagtcac agtctctacc aaaagaagcc
aacaaactgt aaccccgaat atcgggtcta 720gaccctgggt aaggggtctg tccagtagaa
taagcatcta ttggacaata gtaaaaccgg 780gagacatact tttgattaat agcacaggaa
atctaattgc tcctcggggt tacttcaaaa 840tacgaaatgg gaaaagctca ataatgaggt
cagatgtacc cattggcaac tgcagttctg 900aatgcatcac tccaaatgga agcattccca
atgacaaacc ttttcaaaat gtaaacagga 960tcacatatgg ggcctgcccc agatatgtta
agcaaaacac tctgaaattg gcaacaggga 1020tgcggaatgt accagagaaa caaactagag
gcatattcgg cgcaatcgca ggtttcatag 1080aaaatggttg ggagggaatg gtagacggtt
ggtatggttt caggcatcaa aattctgagg 1140gcacaggaca agcagcagat cttaaaagca
ctcaagcagc aatcgaccaa atcaacggga 1200aactgaatag gttaatcgag aaaacgaacg
agaaattcca tcaaatcgaa aaagaattct 1260cagaagtgga agggagaatt caggacctcg
agaaatatgt tgaagacact aaaatagatc 1320tctggtctta caacgcggag cttcttgttg
ccctggagaa ccaacataca attgatctaa 1380ctgactcaga aatgaacaaa ctgtttgaaa
aaacaaggaa gcaactgagg gaaaatgctg 1440aggacatggg caatggttgc ttcaaaatat
accacaaatg tgacaatgcc tgcatagggt 1500caatcagaaa tggaacttat gaccatgatg
tatacagaga cgaagcatta aacaaccggt 1560tccagatcaa aggtgttgag ctgaagtcag
gatacaaaga ttggatccta tggatttcct 1620ttgccatatc atgctttttg ctttgtgttg
ttttgctggg gttcatcatg tgggcctgcc 1680aaaaaggcaa cattaggtgc aacatttgca
tttgagtgca ttaattaaaa a 173141738DNAInfluenza A virus
4agcgaaagca ggggaaacaa tgctatcaat tgtaattttg tttctgctcg tagcagagaa
60ttcttctcaa aactatacag gaaaccctgt gatatgcatg ggacatcatg ctgttgccaa
120tggaaccatg gtaaagaccc taaccgatga tcaagtagaa gtggtcactg cacaagaact
180ggtagaatcg cagaatctcc cggaattatg tccgagtcca ctgagactag ttgatggtca
240gacttgcgat atcatcaatg gagcattggg gagcccagga tgtgaccatc tgaatggtgc
300agaatgggat gtgttcatag aaagacccaa tgcaatggac acctgctatc cattcgatgt
360gccagattac caaagcctga gaagcatact tgcgaacaat gggaaattcg aattcattgc
420agaagaattt caatggacta cagtgaagca aaatgggaaa tctggagctt gcaagagggc
480aaacgtgaat gatttcttta acaggctaaa ttggctggta aagtcagacg gaaatgcgta
540ccctcttcaa aatttgacaa aagtaaataa cggtgattat gcaaggcttt acatttgggg
600ggtccatcac ccttcaacag atacagagca aactaatcta tacaagaaca acccgggaag
660agtcactgtc tctaccaaga ctagccaaac aagtgtagtc cctaacattg gtagcagacc
720ttgggtgaga ggacaaagcg gcaggataag tttctactgg actatcgtag agcctggaga
780cctaatagtc ttcaatacaa tagggaatct aattgcccca agaggacatt acaagctaaa
840caatcagaag aagagtacaa ttctgaacac tgcaattccc ataggctcat gtgttagcaa
900atgtcacaca gacaaaggct ctctctccac gactaaacct ttccagaaca tctcaagaat
960agcaatcggg gattgcccca aatatgttaa acagggatct ttaaaacttg caacagggat
1020gaggaacatc cctgaaaagg catcaagagg actctttgga gcaatagctg gattcataga
1080gaatggctgg cagggcctaa tcgatggttg gtatggattc agacatcaaa atgcagaagg
1140aacaggaact gcagcagacc tcaaatccac ccaggcagcc atcgatcaga tcaatgggaa
1200gttgaaccgt cttatcgaaa agacaaatga gaaataccat caaattgaaa aagagttcga
1260acaggttgag ggaagaattc aagatttaga aaaatatgtt gaggatacaa agattgattt
1320atggtcatat aatgcagaac tgctagtagc actggaaaac cagcacacca tagatgtgac
1380tgattcggag atgaacaaac tttttgaaag agtgaggcgt caactcagag aaaatgctga
1440agacaaagga aatggatgtt tcgagatatt tcacaaatgt gacaacaatt gcattgagag
1500catccggaat ggaacttatg atcatgacat ttacagaaat gaggcaatca acaaccgatt
1560ccaaattcaa ggagtcaaat tgacccaggg atacaaagac atcattcttt ggatttcatt
1620ctccatgtca tgctttttgc tcgttgcact gcttttagcc tttattttgt gggcttgtca
1680aaacggaaac atcaggtgcc agatttgcat ttagagaaaa aacacccttg tttctact
173851734DNAInfluenza A virus 5ccaaactatg aaaatggaaa gaatagtgat
tgccctcgca ataatcagca ttgtcaaagg 60tgaccaaatt tgcattggtt accatgcaaa
caattcaaca gagcaggttg atacaatcat 120ggaaaagaat gtgacggtca cacatgctca
gaatatactg gaaaaagagc acaatgggaa 180actttgcagt cttaaaggag tgaggcccct
cattctgaag gattgcagtg tagctggatg 240gcttcttgga aacccaatgt gtgatgaatt
cctgaatgta ccagaatggt catacatcgt 300ggaaaaagat aatccagtca atggcctgtg
ctatccagga gacttcagcg actacgaaga 360actgaagcat ttaatgagca gcacaaacca
ttttgagaaa attcagataa tccctaggag 420ttcttggtcc aatcatgatg cctcatcagg
agtgagttcg gcatgcccat acaatggtag 480atcttcctta ttcaggaatg tagtgtggtt
gatcaagaag aataatgcgt acccaacagt 540aaagaggacc tataacaaca ccaatgtaga
agacctttta ataatatggg gaatacacca 600ccctaatgat gcagctgaac aaacaaaact
ctaccagaac tcgaacactt atgtgtctgt 660aggaacatca acactgaacc agagatcaat
cccagaaata gccactagac ccaaagtgaa 720cggacaaagt ggaagaatgg aatttttctg
gacaatactg aagtcgaacg atgcaatcag 780ctttgaaagt aatgggaatt ttatagctcc
tgaatatgcg tacaaaattg ccaagaaagg 840agattcagca atcatgagaa gtgaattgga
gtatggtaac tgtgacacca aatgtcagac 900tccattgggt gctataaatt ccagtatgcc
cttccacaat gttcatcctc ttaccattgg 960ggagtgcccc aagtatgtca aatcggacaa
actggtcctt gcaacaggac taagaaacgt 1020accccaaaga gaaacaagag gcctatttgg
tgcaatagca ggattcatag aaggaggatg 1080gcaaggaatg gttgacgggt ggtacggata
ccatcatagc aatgagcagg gaagtggata 1140tgctgcagac aaagaatcta cccagaaagc
aatcgatggg atcaccaata gagtaaactc 1200aatcattgac aaaatgaaca ctcaattcga
agccgttggg aaagaattca acaacctaga 1260aaggagaata gaaaatttga ataagaaaat
ggaagatggg tttttagatg tatggactta 1320caatgcagaa cttctcgtgc tcatggaaaa
cgaaagaact ctggatttcc atgattcaaa 1380tgtcaagaac ctatacgata aggtccgact
ccagctgaga gacaatgcaa aagaattggg 1440caacggatgc ttcgaattct accacaagtg
tgacaatgaa tgcatggaaa gtgtgagaaa 1500tggaacgtat gactatccgc aatattcaga
agaatcaaga ctgaacagag aggaaataga 1560cggagtcaaa ttggaatcaa tgggcaccta
tcagatatta tcaatctact caacagtggc 1620gagttcccta gcactggcaa tcatgatagc
tggtctatct ttttggatgt gctccaatgg 1680atcattgcag tgcagaattt gcatctagaa
ttgtgagttc agattataat taaa 173461706DNAInfluenza A virus
6atgattgcaa tcattgtaat agtgatactg gtaacggccg gaaagtcaga caagatctgc
60atcggatacc atgccaacaa ttcaacaaca caagtggata cgatattgga gaaaaatgta
120accgtcacac actctgttga attgctggaa aatcaaaagg aagaaagatt ctgtcggatt
180ttgaacaagg ccccacttga cttaagagga tgcaccatgg agggttggat attagggaac
240cctcaatgtg acctattact tggtgatcag agttggtcat acatagtgga acggcctaca
300gctcgaaatg ggatctgcta ccctggagtt ttgaatgaag cagaagaatt gaaggcactc
360attggatcag gagaaagagt agagagattt gaaatgtttc ccaaaagcac atggagagga
420gtagacacca gcaacggagt aacagcagct tgcccttaca atagtggttc ttctttctac
480agaaacctgc tatggataat aaaaaccact tcagcacaat atccagtaat tagtggaact
540tacaataaca ctgggaacaa gccaatcctc tatttctggg gtgtacatca tcctcctgat
600accactgaac aaaacaagtt atatggttct ggcgatcgat atgttagaat gggaactgaa
660agcatgaatt ttgccaagag cccggaaatt gcagcaaggc ctgcagtgaa tggccaaaga
720ggcaggattg attattactg gtctgtttta cggccagggg aaacattaaa tgtggaatct
780aatgggaatc taatcgctcc ttggtatgca tacaaatttg acagtaccac tagcaaggga
840gcagtattca agtcagattt gccaatagag agctgcgatg ccacatgtca aactgttgct
900ggagtcctga gaacaaatag aacctttcag aatgtaagcc ccctgtggat aggagagtgt
960cccaaatacg tgaaaagcga aagcttgagg cttgcaactg ggctaagaaa tgtcccaaag
1020gttgatacca gagggctttt cggagccata gcaggtttca tcgaaggggg atggactgga
1080atggtagatg ggtggtatgg ctatcatcat gagaactctc aaggttcggg gtatgcagca
1140gacagggaaa gcacccaaaa ggccatagac gggattacaa ataaggtcaa ttccattata
1200gacaagatga acacacaatt cgaagctgtt gaccatgagt tttcaaactt ggagaggaga
1260attgacaacc tacacaaaag aatggaggat gggtttctgg atgtttggac atacaatgct
1320gaactgttgg ttctcctcga ggacgaaagg acactggaca tgcatgacgc taacgtgaag
1380aatctgtatg aaaaggtcaa atcacaacta cgagacaatg ctaatgatat gggaaatggg
1440tgctttgaat tttggcataa gtgtgatgat gaatgcatgg agtctgtcaa aaatggaact
1500tatgattatc caaaatacca ggatgaaagt aagttaaaca gacaggaaat agaatcagtg
1560aagctggaga atcttggtgt gtatcaaatt cttgccatct atagtacggt atcgagcggt
1620ctagtattgg tggggctgat catagcaatg ggcctttgga tgtgttcgaa tggttcaatg
1680caatgcagga tatgtatata attaag
170671686DNAInfluenza A virus 7atgaacactc aaattctggc attcattgcc
tgtatgctgg ttggagttaa aggagacaaa 60atatgtcttg ggcaccatgc tgtggcaaat
gggacaaaag tgaacacact aacagagagg 120ggaattgaag tcgtgaatgc cacagagacg
gtggagaatg cgaatattaa gaaaatatgc 180actcaagaga aaaggccaac agatctggga
caatgtggac ttctagggac cttaatagga 240cctccccaat gtgaccgatt cctggagttt
gattctgatt taatcattga gcgaagggaa 300ggaaccgatg tgtgctatcc cggaaaattc
acaaatgaag aatcactgag gcagatcctt 360cgagggtcag gaggaattga taaggagtca
ataggtttca cttatagtgg aataagaacc 420aatggagtga caagtgcctg cagaagatta
ggttcttctt ccttctatgc agagatgaag 480tggttactgt cgaattcaga caatgcggca
tttccccaga tgaccaaatc gtatagaaat 540cccaggaaca agccagctct gataatttgg
ggaattcatc actctgcatc ggctaatgag 600cagaccaaac tctatggaag tggaaacaaa
ttgataacag taggaagctc gaaataccag 660caatcattca ctccaagtcc gggagcacgg
ccacaagtga atggacaaac agggaggatc 720gatttccact ggctgctcct tgatcccaat
gacacggtga ccttcacctt caatggagca 780ttcatagccc ctgacagggc aagtttcttt
agaggggaat cgctaggaat ccagagtgat 840gttcctttgg attctagttg tgggggagac
tgctttcaca gcgggggtac gatagtaagt 900tccctgccat tccaaaacat caaccctaga
actgtgggga aatgccctcg atatgtcaaa 960cagacaagcc tccttttggc tacaggaatg
agaaatgtcc cagagaatcc caagaccagg 1020ggtctctttg gagcaattgc tggattcata
gagaatggat gggagggtct cattgatgga 1080tggtatggtt tcaaacatca aaatgcgcaa
ggagaaggaa ctgcagctga ttataaaagc 1140acccaatctg caatagatca gatcacaggc
aaattgaatc gtttgatcga caaaacaaat 1200cagcagtttg agctgataga caatgagttc
aatgaaatag aacaacaaat cggaaatgtc 1260attaattgga cacgagattc aatgactgaa
gtgtggtcgt acaatgctga actgttggtg 1320gcaatggaaa atcagcatac catagatctt
gcggactcag aaatgaacaa actttatgag 1380cgtgtcagga aacaactaag ggagaatgct
gaagaagatg gaactggatg ttttgagata 1440ttccataagt gtgatgatca gtgtatggag
agcataagga acaacactta tgaccatact 1500caatacagaa cagagtcatt acagaataga
atacagatag acccagtgaa attgagtagt 1560gggtacaaag acataatctt atggtttagc
ttcggggcat catgtttcct tcttctagcc 1620attgcaatgg gattgatctt catttgcata
aagaatggaa acatgcggtg cactatttgt 1680atatag
168681672DNAInfluenza A virus
8ctcttggtga gcacaaatgc atacgatagg atatgcattg gttaccaatc aaacaactcc
60acagacacag tgaacaccct tatagaacag aatgtgccag tcactcaaac aatggagctc
120gtggaaacgg agaaacatcc cgcttattgc aacactgatt taggatcacc attggaacta
180cgagactgca aaattgaagc agtaatctat ggaaatccca agtgtgacat ccatctaaag
240gaccaagatt ggtcatacat agtggagagg cccagtgcac cagagggaat gtgttaccct
300ggatctgtgg aaaatctaga agaactgaga ttcgtcttct ccaatgctgc atcctacaag
360agaataagac tatttgacta ttccaaatgg aatgtgacca gctctgggac cagcaaggca
420tgcaatgcat caacaggtgg ccaatcattc tataggagca tcaactggtt gaccaagaaa
480aaaccagaca cttacgattt caatgaaggg agttatgtta acaatgagga tggagacatc
540attttcttat gggggattca tcatccacct gatgcaaaag agcaaacgac actgtacaag
600aatgcaaaca ccttgagtag tgttactacc aacaccataa atagaagttt tcaacccaat
660attggtccaa ggccattagt cagaggacaa caagggagaa tggattacta ctggggcatt
720ctgaaaaggg gagagactct gaaaattagg actaatggaa atttaattgc acctgaattt
780ggatatttac ttaagggtga gagccatggc agaataattc aaaatgagga catccccatt
840ggaaactgcc acacaaaatg ccagacatat gcaggagcaa tcaatagcag caaacccttt
900cagaatgcca gtagacatta tatgggggag tgtcccaaat atgtaaaaaa ggcaagcttg
960cgacttgcag tgggacttag aaacacacct tctattgaac ccaaagggct atttggagcc
1020attgctggtt tcatcgaggg aggatggtct gggatgattg atggatggta tggatttcac
1080cacagcaact cagagggaac aggaatggca gctgaccaga agtcaacaca ggaagccatc
1140gataagatca ccaataaagt caacaatata gttgataaga tgaacaggga gtttgaagtt
1200gtgaatcatg agttctctga agttgaaaaa aggataaaca tgataaatga taaaatagat
1260gaccaaattg aagatctttg ggcttacaat gcagaactcc ttgtgcttct agaaaaccag
1320aagacactag acgaacatga ctccaatgtc aaaaatcttt tcgatgaggt gaaaagaaga
1380ttgtcggcca atgcaataga tgctgggaat ggttgctttg acatactcca caagtgcaac
1440aatgagtgta tggaaactat aaagaatggg acttacgacc ataaggagta tgaagaggag
1500gctaaattag aaaggagcaa aataaatggg gtgaaactgg aagagaacac cacttacaaa
1560attcttagca tttacagtac agtggcggcc agtctctgct tggcaatcct gattgctgga
1620ggtttaatcc tgggtatgca aaatggatct tgtagatgca tgttctgtat tt
167291683DNAInfluenza A virus 9atggaaacag tattgctaat aactatacta
ctagtagtaa cagtaagcaa tgcagataaa 60atctgcatcg gctaccaatc aacaaactcc
acagaaactg tagacacgct aacagaaaac 120aatgtccctg tgacacatgc caaagaattg
ctccacacag agcacaatgg gatgctgtgt 180gcaacaaatc tgggacatcc tctcattcta
gacacctgta ccattgaagg actaatctat 240ggcaaccctt cttgtgatct actgttggga
ggaagagaat ggtcctacat cgttgaaaga 300ccatcggctg ttaatggatt gtgttacccc
gggaatgtag aaaacctaga agaactaagg 360tcacttttta gttctgctag ttcttaccaa
agaatccaga tctttccaga cacaatctgg 420aatgtgtctt acagtgggac aagcaaagca
tgttcagatt cattctacag aaacatgaga 480tggttgactc aaaagaacaa cgcataccct
attcaagacg cccaatacac aaataatcga 540gggaagaaca ttcttttcat gtggggcata
aatcacccac ccaccgatac tacgcagaca 600aatctgtaca caaggactga cacaacaaca
agtgtggcaa cagaagatat aaataggacc 660ttcaaaccat tgatagggcc acggcctctt
gtcaatggtc agcagggaag aattgattat 720tattggtcgg tattgaaacc aggtcaaaca
ctgcgagtaa ggtccaatgg gaatctaatt 780gctccattgt atggacacat cctttcagga
gagagccacg gaagaatcct gaagactgat 840ttaaaaagtg gtaactgtgc agtgcaatgt
cagacagaaa gaggtggctt aaatacaaca 900ttgccattcc aaaatgtaag taagtatgca
tttggaaact gcccgaaata tgttggagta 960aagagtctca aactggcagt tggtctgagg
aatgtgcctg ctagatcaag tagaggacta 1020ttcggggcca tagctggatt catagaggga
ggttggtcag ggctagtcgc tggttggtat 1080gggttccagc attcaaatga tcaaggggtt
ggtatggcag cagatagaga ctcaactcaa 1140aaggcaattg acaaaataac atccaaagtg
aataatatag tcgataaaat gaacaaacag 1200tatgaaatta ttgatcatga attcagcgag
gttgaaacta gaatcaacat gatcaataat 1260aagattgatg accaaattca agacatatgg
gcatataacg cagaattgct agtgctgctt 1320gaaaaccaga aaacactcga tgagcatgat
gcgaatgtaa acaatctata taataaagtg 1380aagagggcat tgggttccaa tgcagtggaa
gatgggaaag gatgtttcga gctataccat 1440aaatgtgatg accagtgcat ggagacaatt
cggaacggga cctacaacag gaggaagtat 1500aaagaggaat caagattaga aagacagaaa
atagaagggg tcaagctgga atctgaagga 1560acttacaaaa tcctcaccat ttattcgact
gtcgcctcat ctcttgtgat tgcaatgggg 1620tttgctgcct tcttgttctg ggccatgtcc
aatggatctt gcagatgcaa catttgtata 1680taa
1683101760DNAInfluenza A virus
10atgtacaaac ttgtagcagt aattgcgctc cttggagcag tgagaggtct tgacaaaatc
60tgtctaggac atcatgcagt agccaatgga accatcgtga agacccttac aaatgaacag
120gaagaggtga ccaatgctac tgaaacagtg gagagcacaa gtctaaacag gttatgtatg
180aagggaagaa gctataagga tctgggcaat tgccatccaa taggaatgtt gataggaaca
240ccagcttgtg atctgcatct tactgggaca tgggacactc tcattgagcg agagaatgcc
300attgcctact gttaccctgg agcgaccgta aatgaagaag cactgaggca gaaaataatg
360gagagtgggg gaatcagcaa aataagcact ggcttcactt atgggtcttc catcaactca
420gccggaacca ctaaagcatg catgagaaat ggaggaaata gcttttatgc agagctcaaa
480tggctagtat caaagagtaa gggacaaaac ttccctcaga ccacgaacac ttatagaaac
540acggacacag ctgaacatct cataatatgg ggaatccatc acccttccag cactcaggag
600aagaatgatc tatatgggac acaatcacta tctatatcag ttgggagttc cacatatcag
660aacaattttg ttccagttgt tggggcaaga cctcaggtca atggacaaag cgggcgaatt
720gatttccact ggacattagt acaaccaggc gataatatca ctttctcaca caatgggggt
780ctgatagcac cgagtcgagt tagcaaacta gttggaagag gattgggagt tcaatcagaa
840gcatcaatag acaatggttg tgaatctaaa tgtttttgga gaggaggctc cataaataca
900aagctccctt tccaaaattt gtcaccaagg acagtgggtc agtgtcccaa atacgtgaat
960aagaagagtt tgatgcttgc aacaggaatg agaaatgtac cagaaataat gcaagggaga
1020ggtctatttg gtgcaatagc aggatttata gaaaatggat gggaaggaat ggtggatggt
1080tggtatggtt tcagacacca aaatgctcag gggacaggcc tagccgccga ttacaagagt
1140actcaggcag ctatcgacca aatcactggg aagctgaaca ggctgattga gaagaccaac
1200actgagtttg agtcaataga gtctgagttc agtgagattg aacatcagat tggtaacgtc
1260attaattgga ccaaggattc aataaccgac atctggactt atcaggaaga actattggta
1320gcaatggaga accagcatac aattgacatg gctgattcag agatgctaaa tttgtatgag
1380agagtgagga aacaactcag gcagaatgca gaagaagatg ggaaggggtg ttttgagata
1440tatcatactt gtgacgattc gtgcatggag agcataagga acaacaccta tgaccattca
1500caatacagag aggaagctct tttgaataga ctgaacatca attcagtaaa actttcttcg
1560ggttataaag acatcatcct ttggtttagc ttcggggcat catgctttgt tcttctggcc
1620gttgtcatgg gtcttgtttt cttctgtctg aaaaatggaa acatgcgacg cacaatctgt
1680atttagttaa aaacacccaa acccccttgg gaccctgaga ggcaccccca agaattagta
1740aaaaaccccc caaaattttt
1760111727DNAInfluenza A virus 11aatatcaaga aatcaagatg aagaaagtac
tgctctttgc aacaatcatc atctgcatcc 60aagcagacga gatctgcatt gggtacctga
gcaacaactc aacagaaaaa gtggacacaa 120taattgagag taatgtcacg gttactagct
cagttgaact ggttgaaaat gagcacactg 180gatctttctg ctcaatcgac gggaaagcac
cgataagtct tggtgattgc tcctttgctg 240gatggatcct tggaaaccca atgtgtgatg
atttgattga gaaaacatca tggtcctaca 300tagtggagaa accaaatccc gtcaatggaa
tatgttaccc gggtactcta gaaaatgagg 360aggaattgag actgaagttt agtggagtcc
tcgaattcag taaatttgaa gccctcacct 420caaatggatg gggagcagta aattctggtg
ctggtgttac cgcagcctgc aaatttggaa 480gcagtaactc ttttttcagg aacatggtat
ggttgatcca ccaatcaggg acatatcctg 540ttatacggag gacattcaac aacaccaaag
gaagagatgt attaatggta tggggagttc 600accaccccgc aaccctaaag gaacaccaag
acttgtacaa aaaagacagt tcttatgtag 660cagtaggttc agagagttac aacaggaggt
tcactcctga gatcagtaca aggcctaaag 720taaatggtca ggctgggaga atgacattct
actggaccat agtgaaaccg ggagaagcaa 780taacatttga gtcaaatggt gcatttctcg
ctcctcggta tgcttttgag ttagtatcct 840tggggaatgg gaaattgttc aggagtgatt
tgaatattga atcttgctca actaaatgcc 900agtccgaaat tggagggatc aacactaata
ggagcttcca caatgtccat aggaacacaa 960taggagactg ccccaaatat gtgaatgtta
aatctctaaa gcttgctacc gggctcagaa 1020atgtccctgc gattgctaca agaggcctgt
ttggtgcaat agctggtttc atagaaggtg 1080gttggccagg tttaatcaat ggttggtatg
ggttccaaca cagaaatgaa gaaggtacag 1140ggattgctgc agacaaagaa tcaacccaga
aagcaataga ccagataaca tctaaagtca 1200acaacattgt tgatcggatg aatacgaact
ttgagtctgt tcaacatgaa tccagtgaaa 1260ttgaagagag aataaaccaa ttgtcaaaac
atgttgatga ttctgttatt gacatatggt 1320catacaacgc acagcttctt gttctattgg
aaaatgaaaa aacattagat ctccatgatt 1380ctaatgttcg aaacctccat gaaaaggtca
gacgaatgct gaaggacaat gctaaagatg 1440aagggaatgg ttgttttact ttctatcaca
agtgtgataa tgaatgtatt gaaaaagtca 1500ggaatggaac atatgaccac aaggaatttg
aagaggagtc caaattgaat agacaagaaa 1560ttgagggagt gaaactggat tccaatggca
acgtttacaa aatactgtca atttacagct 1620gcattgcaag cagtcttgtg ttggcagcaa
tcattatggg attcatcttc tgggcgtgta 1680gcaatgggtc atgtagatgt accatttgca
tttagaattg caataaa 1727121712DNAInfluenza A virus
12ggtcacaatg gaaaaattca tcattttgag cactgtcctg gcagtaaact ttgcatatga
60caaaatttgc attggatatc agacaaacaa ctcgactgag acagtaaaca cactaatcga
120gcaaaacgtt ccggtgacac aggtggaaga actcgtgcat ggtggaatcg atccggtcct
180atgtggaacg gagctagggt caccattagt gcttgatgat tgttcactcg aaggtctcat
240tctaggcaat cccaaatgtg atctttatct gaatggcagg gaatggtcat acatagtaga
300gaggcccaaa gaaatggaag gagtttgcta cccaggatca attaaaaatc aagaggagtt
360gagatctctg ttttcttcca tcaagaagta tgaaagagtg aagatgtttg atttcaccaa
420atggaatgtc acgtacactg gaaccagcaa ggcctgcaac aatacatcaa accaaggctc
480attctatagg agcatgagat ggttaacctt aaaatcagga caattcccag tccaaacaga
540tgagtacaag aacaccagag attcggacat tgttttcacc tgggccatcc atcacccacc
600aacatctgat gaacagataa aattatacaa aaatccggat accctctcct cagtcaccac
660tgatgaaatc aataggagtt tcaagcctaa cataggacca aggccattag tgagaggaca
720gcaggggaga atggattact actgggctgt cctcaaacct ggacaaactg tcaaaataca
780gaccaatggt aatcttattg cacctgaata tggtcactta atcacaggga aatcacatgg
840caggatactc aagaataact tgcccatagg acagtgtgtg actgaatgcc aattgaatga
900aggggtgatg aatacaagta aacctttcca gaacactagt aagcactata ttgggaaatg
960tcccaaatac ataccatcgg gaagcctgaa attggcgata gggctcagaa atgttccaca
1020agttcagaac aggggactat ttggagcaat tgcaggtttc atagagggcg gatggccagg
1080actagtggct gggtggtatg gatttcagca tcaaaatgca gaggggacag gcatagccgc
1140agacagagac agcactcaga aggcaataga caatatgcaa aacaaactca acaatgtcat
1200tgacaaaatg aacaaacaat ttgaagtggt gaatcatgag ttttcagaag tggaaagcag
1260aataaacatg attaattcca aaattgatga tcaaataact gacatatggg catacaatgc
1320tgaactgctt gttctattgg aaaatcagaa gacattagat gagcatgatg ctaatgtaag
1380aaacttacac gatagagtca gaagagtcct aagagaaaat gcaattgata caggagatgg
1440ttgctttgaa attctgcata aatgtgacaa caattgcatg gacacaatca gaaatgggac
1500atacaatcac aaggagtatg aggaagaaag caaaattgaa cgacagaaaa ttaatggtgt
1560caaacttgag gagaattcta catataaaat tctgagcatc tacagcagtg ttgcctcaag
1620cttagttcta ctgctcatga ttattggggg tttcattttc ggatgtcaaa atggaaatgt
1680tcgttgtact ttctgtattt aattaaaaac ac
1712131765DNAInfluenza A virus 13agcaaaagca gggaaaattt caacaaactg
acacaagaga aatggacatc caagcagtcg 60cactcttgat attaaccagc acatgcgtac
aggctgatag aatctgtgtg ggatacttaa 120gcaccaactc atcagaaaaa gttaacacac
tgttagagaa cgatgtcccg gttacaagtt 180ctgtcgatct ggttgagact agccacacag
gaacatattg ttctttggat ggaatcagtc 240cagtgcattt gggagactgt agcttcgagg
gttggattgt agggaaccct gcctgtgcca 300gcaacatggg gatcagagaa tggtcatact
tgattgaaga tccctctgca cctcatggac 360tgtgctaccc aggagagtta gacaacaatg
gagaattgag gcacctgttc agtggaatca 420gatctttcag tagaacagag ttgatcgcac
ctacttcttg gggggcagtg aatgatggag 480tatcatcggc ctgccaggat cgaggggcca
gcagctttta tcgaaatttg gtatggtttg 540tggagagagg caagcaatat ccagtgatcc
gcgggaccta caacaataca actggcagag 600atgttttggt catgtggggg atacatcatc
ctgtttccac agacgaggcg agaaaactat 660atgtcaacaa tgacccatat acattggtat
ctaccagttc atggagtaga aaatacaact 720tagaaattgg aatccggcct ggatacaatg
gccaaaagag ttggatgaag atttactggt 780atttgatgca cccaggggaa tcaatcagtt
tcgaaagcaa tggaggattg ttggccccca 840gatatggtta tattattgag gaatatggaa
aagggcgaat tttccaaagt cgcattcgca 900ttgctaaatg caatactaag tgtcagacat
ctgttggtgg gataaatacc aacaaaacat 960ttcaaaacat agagagaaat gcacttgggg
attgcccaaa atacataaaa tctgggcagc 1020tcaagttggc caccggactt agaaatgtac
ctgccatatc aaacagagga ttatttggag 1080ctattgcagg cttcatagaa ggtggttggc
caggattaat aaatggttgg tatggattcc 1140aacatcagaa cgaacaagga gtgggaatgg
ctgcagacaa agagtcaaca caaaaggcta 1200ttgatcaaat aacaaccaag ataaacaata
tcattgaaaa aatgaatgga aattatgact 1260ccatacgagg tgaattcaat caagtggaac
aaaggataaa tatgcttgca gacagaatag 1320atgacgctgt aactgatgta tggtcataca
atgcaaagct tcttgtgttg ctagagaacg 1380ataaaactct agacatgcat gatgccaatg
ttagaaacct gcatgaccaa gtacgtagag 1440cactaaagac caatgcaatt gatgagggga
atggatgctt tgaactcctc cataaatgca 1500atgactcttg catggagaca ataagaaatg
ggacgtacaa tcacacagaa tatgaagaag 1560aatcaaaatt gaagagacag gaaatagaag
gtataaagct gaagtcagac gataatgttt 1620acaaagcatt atcgatttac agctgcattg
caagcagtat tgtaatggta ggactcatac 1680ttgcattcat catgtggaca tgcaacagtg
gaaactgccg gttcaatatc tgtatataag 1740tagaaaaaat acccttgttt ctact
1765141749DNAInfluenza A virus
14agcaaaagca ggggaaaatg attgcactca tattggttgc actggctctg agccacactg
60cttattctca gatcacaaat gggacaacag gaaaccccat tatatgcttg gggcatcatg
120cagtggaaaa cggcacatct gttaaaacac taacagacaa tcacgtagaa gttgtgtcag
180ctaaagaatt agttgagacg aaccacactg atgaactgtg cccaagcccc ttgaagcttg
240tcgacgggca agactgccac ctcatcaatg gtgcattggg gagtccaggc tgtgaccgtt
300tgcaggacac cacttgggat gtcttcattg aaaggcccac tgcagtagac acatgttatc
360cattcgacgt cccagattac cagagtctca gaagcatcct agcaagcagt gggagtttgg
420agttcatcgc cgaacaattc acctggaatg gtgtcaaagt tgacggatca agcagtgctt
480gtttgagggg cggtcgcaac agcttcttct cccgactaaa ctggctaacc aaagcaacaa
540atggaaacta tggacctatt aacgtcacta aagaaaatac gggctcttat gtcaggctct
600atctctgggg agtgcatcac ccatcaagcg ataatgagca aacggatctc tacaaggtgg
660caacagggag agtaacagta tctacccgct cggaccaaat cagtattgtt cccaatatag
720gaagtagacc gagggtaagg aatcagagcg gcaggataag catctactgg accctagtaa
780acccagggga ctccatcatt ttcaacagta ttgggaattt gattgcacca agaggccact
840acaaaataag caaatctact aagagcacag tgcttaaaag tgacaaaagg attgggtcat
900gcacaagccc ttgcttaact gataaaggtt cgatccaaag tgacaaacct tttcagaatg
960tatcaaggat tgctatagga aactgcccga aatatgtaaa gcaagggtcc ctgatgttag
1020caactggaat gcgcaacatc cctggcaaac aggcaaaggg cttatttggg gcaattgctg
1080gattcattga aaatggttgg caaggcctga ttgatgggtg gtatggattc aggcaccaaa
1140atgctgaagg aacaggaact gctgcagacc tgaagtcaac tcaggcagcc attgatcaga
1200taaatggcaa gctgaacaga ttgatagaga agacaaatga aaaatatcac caaatagaaa
1260aggaattcga acaggtggaa ggaagaatac aagaccttga gaagtacgtt gaggacacta
1320agattgattt gtggtcatac aatgctgaat tgctagtagc actagagaat cagcacacaa
1380tagatgtcac agactccgaa atgaacaagc tttttgaaag agtaagaagg caattaagag
1440agaatgcaga agatcaaggc aacggttgtt tcgagatatt ccatcagtgt gacaacaatt
1500gtatagaaag cattagaaac ggaacttatg accacaacat ctacagggat gaagccatca
1560acaatcgaat caaaataaat cctgtcactt tgacgatggg gtacaaggac ataatcctgt
1620ggatttcttt ctccatgtca tgctttgtct tcgtggcact gattctggga tttgttctat
1680gggcttgtca aaacgggaat atccgatgcc aaatctgtat ataaagaaaa aacacccttg
1740tttctactc
1749151762DNAInfluenza A virus 15agcaaaagca ggggatacaa aatgaacact
caaatcattg tcattctagt cctcggactg 60tcaatggtga aatctgacaa gatttgtctc
gggcaccatg ccgtagcaaa tgggacaaaa 120gtcaacacac taactgagag aggagtggaa
gtggtcaatg ccacggagac agtggagatt 180accggaatag ataaagtgtg cacaaaaggg
aagaaagcag tggacctggg atcttgtgga 240atactgggaa ctatcattgg gcctccacaa
tgtgatcttc atcttgaatt caaagctgat 300ctgataatag aaagaagaaa ttcaagtgac
atctgttacc caggaagatt cactaatgag 360gaagcactga gacaaataat cagagaatct
ggaggaattg acaaagagtc aatgggcttt 420agatattcag gaataagaac agacggggca
accagtgcgt gtaagagaac agtgtcctct 480ttctactcag aaatgaaatg gctttcatcc
agcatgaata accaggtgtt cccacaactg 540aatcagacat acaggaacac cagaaaagaa
ccagccctaa ttgtctgggg agtacatcat 600tcaagttcct tggatgagca aaataagcta
tatggaactg ggaacaagct gataacagta 660ggaagctcaa agtaccaaca atcgttttca
ccaagtccag gggccaggcc caaagtgaat 720ggtcaggccg ggaggatcga ctttcattgg
atgctattgg acccagggga tacagtcact 780tttaccttca atggtgcatt catagcccca
gatagagcca cctttctccg ctctaatgcc 840ccttcaggaa ttgagtacaa tgggaagtca
ctgggaatac agagtgatgc acaaatcgat 900gaatcatgtg aaggggaatg cttctacagt
ggagggacaa taaacagccc tttaccattt 960caaaacatcg atagtagggc tgtcggaaag
tgccccagat atgtgaagca atcaagcttg 1020ccgctggcct taggaatgaa aaatgtacca
gagaaaatac gtactagggg actgttcggt 1080gcaattgcag gattcatcga aaatggatgg
gaagggctca ttgatggatg gtatggattt 1140aggcatcaga atgcacaagg gcagggaaca
gctgctgact acaagagtac tcaggctgca 1200attgaccaga taacagggaa acttaatagg
ttaattgaaa aaaccaacaa acagtttgaa 1260ctcatagaca atgagttcac tgaagtggag
cagcagatag gcaatgtaat aaactggaca 1320agggactcct tgactgagat ctggtcatac
aatgccgaac tgctagtagc aatggagaat 1380cagcatacaa ttgaccttgc agattctgaa
atgaacaaac tctatgagag agtgagaaga 1440cagctaaggg agaatgccga ggaggatgga
actggatgtt ttgagatttt ccaccgatgt 1500gacgatcaat gtatggagag catacggaat
aatacttaca atcacactga atatcgacag 1560gaagccttac aaaataggat aatgatcaat
ccggtaaagc ttagtagtgg gtacaaagat 1620gtgatactat ggtttagctt cggggcatca
tgtgtaatgc ttctagccat tgctatgggt 1680cttattttca tgtgtgtgaa aaacgggaat
ctgcggtgca ctatctgtat ataattattt 1740gaaaaacacc cttgtttcta ct
1762161718DNAInfluenza A virus
16atgatgatta aagtgctcta ctttctcatc atagtgcttg gcaggtattc aaaagcagac
60aaaatatgca taggatacct aagcaataat tcttcagata cagtggacac actaacagag
120aacggagttc ctgtgaccag ctcagttgat ctcgttgaaa caaatcatac tggaacatac
180tgctcattga atggtatcag tccgattcat cttggtgact gcagctttga gggatggatt
240gtaggaaacc cctcctgtgc caccaacatc aacatcagag agtggtcata tttaattgaa
300gaccctaatg cccccaacaa actctgctac ccaggggagt tagacaacaa tggagaacta
360cgacacctct tcagcggagt gaactctttt agcagaacag aactgataaa tcccagcaaa
420tggggaaatg ttctggatgg agtcactgct tcttgcctcg atagaggggc aagcagtttt
480tacaggaact tggtctggct agtgaagcaa aaaattggag aatatcctgt tgtaaaaggg
540gaatacaaca acacaacggg cagagatgtt ctagtacttt gggggattca ccatccggat
600acagaaacaa cagccacaaa cctatatgtc aacaaaaacc cctacacact agtatcaaca
660aaggagtgga gcaaacggta tgaacttgaa attggaacca gaataggcga tggacagaga
720agttggatga aactatattg gcatctcatg cacccgggag aaaggataat gtttgagagt
780aatgggggcc ttatagcacc cagatatgga tacatcattg agaaatacgg aacgggacga
840attttccaaa gtggagtgag aatggccaaa tgcaacacaa agtgtcaaac gtcattaggt
900gggataaaca ctaacaaaac tttccagaac atagaaagaa atgcccttgg ggactgccca
960aagtacataa agtctggaca actgaagctt gcaactggac tgagaaatgt tcccattccc
1020attggtgaaa gaggtctgtt tggtgcaatt gcaggcttca tagaaggagg gtggcctggt
1080ctaattaatg gatggtatgg tttccaacat cagaacgaac aggggacggg cattgctgcg
1140gataaagctt ccactcagaa agcaataaat gaaataacaa caaagattaa caacataata
1200gagaagatga acggaaacta tgattcgata agaggggaat tcaatcaagt agagaagagg
1260attaacatgc tcgccgatcg agttgatgat gcagtaactg atatatggtc gtacaatgct
1320aaacttcttg tactaattga aaatgataga acgctggact tgcatgacgc aaatgtcaga
1380aacttacatg atcaggtcaa gagggcattg aaaagtaatg ccattgatga aggagatggt
1440tgcttcaatc ttcttcacaa atgcaatgac tcatgcatgg aaaccattag aaatgggacc
1500tacaatcatg aagattacag ggaagaatca caactgaaga ggcaggagat tgaggggata
1560aaattaaaga ctgaagacaa tgtttataaa gtactgtcaa tttatagctg cattgcaagc
1620agtattgtgc tggtaggtct catacttgca tttataatgt gggcatgcag caatgggagt
1680tgccggttta atgtttgtat ataatcggaa aaaacacc
1718171793DNAInfluenza B virus 17caaaatgaag gcaataattg tactactcat
ggtagtaaca tccaatgcag atcgaatctg 60cactgggata acatcgtcaa actcaccaca
tgtcgtcaaa actgctactc aaggggaggt 120caatgtgact ggtgtaatac cactgacaac
aacacccacc aaatctcatt ttgcaaatct 180caaaggaaca gaaaccagag ggaaactatg
cccaaaatgc ctcaactgca cagatctgga 240cgtagccttg ggcagaccaa aatgcacggg
gaaaataccc tcggcaagag tttcaatact 300ccatgaagta agacctgtta catctgggtg
ctttcctata atgcacgaca gaacaaaaat 360tagacagctg cccaaccttc tccgaggata
cgaacatatc aggttatcaa ctaataacgt 420tatcaatgca gaaaatgcac caggaggacc
ctacaaaatt ggaacctcag ggtcttgccc 480taacgttacc aatggaaacg gatttttcgc
aacaatggct tgggccgtcc caaaaaacga 540caaaaacaaa acagcaacaa atccattaac
aatagaagta ccatacattt gtacagaagg 600agaagaccaa attaccgttt gggggttcca
ctctgataac gagatccaaa tggcaaagct 660ctatggggac tcaaggcccc agaagttcac
ctcatctgcc aacggagtga ccacacatta 720cgtttcacag attggtggct tcccaaatca
aacagaagac ggaggactac cacaaagtgg 780tagaattgtt gttgattaca tggtgcaaaa
atctgggaaa acaggaacaa ttacctatca 840aagaggtatt ttattgcctc aaaaggtgtg
gtgcgcaagt ggcaggagca aggtaataaa 900aggatccttg cctttaattg gagaagcaga
ttgcctccac gaaaaatacg gtggattaaa 960caaaagcaag ccttactaca caggggaaca
tgcaaaggcc ataggaaatt gcccaatatg 1020ggtgaagaca cccttgaagt tggccaatgg
gaccaaatat agacctcctg caaagctatt 1080aaaggaaagg ggtttcttcg gagctattgc
tggtttctta gaaggaggat gggaaggaat 1140gattgcaggt tggcacggat acacgtccca
tggggcacat ggagtagcgg tggcagcaga 1200ccttaagagc acccaagagg ccataaacaa
gataacaaaa aatctcaact ctttgagtga 1260gctggaagta aagaatcttc aaagactaag
cggtgccatg gatgaactcc acaacgaaat 1320actagaacta gacgagaaag tggatgatct
cagagctgac acaataagct cacaaataga 1380actcgcagtc ctgctttcca atgaaggaat
aataaacagt gaagatgaac atctcttggc 1440gcttgaaaga aagctgaaga aaatgctggg
cccctctgct gtagagatag ggaatggatg 1500ctttgaaacc aaacacaagt gtaaccagac
ctgtctcgac agaatagctg ctggtacctt 1560tgatgcagga gaattttctc tccccacctt
tgattcactg aatattactg ctgcatcttt 1620aaatgacgat ggattggata atcatactat
actgctttac tactcaactg ctgcctccag 1680tttggctgta acactgatga tagctatctt
tgttgtttat atggtctcca gagacaatgt 1740ttcttgctcc atctgtctat aagggaagtt
aagccctgta ttttccttta ttg 1793183417DNAArtificial
SequenceChimeric sequences 18atgaagacca tcattgcttt gagctacatt ttctgtctgg
ctctcggcgc cagcacccag 60agccccagcg tgttccccct gacccgctgc tgcaagaaca
tccccagcaa cgccaccagc 120gtgaccctgg gctgcctggc caccggctac ttccccgagc
ccgtgatggt gacctgggac 180accggcagcc tgaacggcac caccatgacc ctgcccgcca
ccaccctgac cctgagcggc 240cactacgcca ccatcagcct gctgaccgtg agcggcgcct
gggccaagca gatgttcacc 300tgccgcgtgg cccacacccc cagcagcacc gactgggtgg
acaacaagac cttcagcgtg 360tgcagccgcg acttcacccc ccccaccgtg aagatcctgc
agagcagctg cgacggcggc 420ggccacttcc cccccaccat ccagctgctg tgcctggtga
gcggctacac ccccggcacc 480atcaacatca cctggctgga ggacggccag gtgatggacg
tggacctgag caccgccagc 540accacccagg agggcgagct ggccagcacc cagagcgagc
tgaccctgag ccagaagcac 600tggctgagcg accgcaccta cacctgccag gtgacctacc
agggccacac cttcgaggac 660agcaccaaga agtgcgccga cagcaacccc cgcggcgtga
gcgcctacct gagccgcccc 720agccccttcg acctgttcat ccgcaagagc cccaccatca
cctgcctggt ggtggacctg 780gcccccagca agggcaccgt gaacctgacc tggagccgcg
ccagcggcaa gcccgtgaac 840cacagcaccc gcaaggagga gaagcagcgc aacggcaccc
tgaccgtgac cagcaccctg 900cccgtgggca cccgcgactg gatcgagggc gagacctacc
agtgccgcgt gacccacccc 960cacctgcccc gcgccctgat gcgcagcacc accaagacca
gcggcccccg cgccgccccc 1020gaggtgtacg ccttcgccac ccccgagtgg cccggcagcc
gcgacaagcg caccctggcc 1080tgcctgatcc agaacttcat gcccgaggac atcagcgtgc
agtggctgca caacgaggtg 1140cagctgcccg acgcccgcca cagcaccacc cagccccgca
agaccaaggg cagcggcttc 1200ttcgtgttca gccgcctgga ggtgacccgc gccgagtggg
agcagaagga cgagttcatc 1260tgccgcgccg tgcacgaggc cgccagcccc agccagaccg
tgcagcgcgc cgtgagcgtg 1320aaccccggca agggagcagc ttcttcagca gctggtggag
cagcttcttc agcagctggt 1380ggagcagctt cttcagcagc tggtggagca gcttcttcag
cagctggtgc cagcacccag 1440agccccagcg tgttccccct gacccgctgc tgcaagaaca
tccccagcaa cgccaccagc 1500gtgaccctgg gctgcctggc caccggctac ttccccgagc
ccgtgatggt gacctgggac 1560accggcagcc tgaacggcac caccatgacc ctgcccgcca
ccaccctgac cctgagcggc 1620cactacgcca ccatcagcct gctgaccgtg agcggcgcct
gggccaagca gatgttcacc 1680tgccgcgtgg cccacacccc cagcagcacc gactgggtgg
acaacaagac cttcagcgtg 1740tgcagccgcg acttcacccc ccccaccgtg aagatcctgc
agagcagctg cgacggcggc 1800ggccacttcc cccccaccat ccagctgctg tgcctggtga
gcggctacac ccccggcacc 1860atcaacatca cctggctgga ggacggccag gtgatggacg
tggacctgag caccgccagc 1920accacccagg agggcgagct ggccagcacc cagagcgagc
tgaccctgag ccagaagcac 1980tggctgagcg accgcaccta cacctgccag gtgacctacc
agggccacac cttcgaggac 2040agcaccaaga agtgcgccga cagcaacccc cgcggcgtga
gcgcctacct gagccgcccc 2100agccccttcg acctgttcat ccgcaagagc cccaccatca
cctgcctggt ggtggacctg 2160gcccccagca agggcaccgt gaacctgacc tggagccgcg
ccagcggcaa gcccgtgaac 2220cacagcaccc gcaaggagga gaagcagcgc aacggcaccc
tgaccgtgac cagcaccctg 2280cccgtgggca cccgcgactg gatcgagggc gagacctacc
agtgccgcgt gacccacccc 2340cacctgcccc gcgccctgat gcgcagcacc accaagacca
gcggcccccg cgccgccccc 2400gaggtgtacg ccttcgccac ccccgagtgg cccggcagcc
gcgacaagcg caccctggcc 2460tgcctgatcc agaacttcat gcccgaggac atcagcgtgc
agtggctgca caacgaggtg 2520cagctgcccg acgcccgcca cagcaccacc cagccccgca
agaccaaggg cagcggcttc 2580ttcgtgttca gccgcctgga ggtgacccgc gccgagtggg
agcagaagga cgagttcatc 2640tgccgcgccg tgcacgaggc cgccagcccc agccagaccg
tgcagcgcgc cgtgagcgtg 2700aaccccggca agaattcctg cagcccgggg gatcgagagt
gtcgtagaaa gaagaaagaa 2760tatgtgaaat gtttagaaaa cagagtggca gtgcttgaaa
atcaaaacaa gacattgatt 2820gaggagctaa aagcacttaa ggacctttac tgccacaaat
cagatggtga tgctgcagca 2880gatggttata taaaattatt cataatgata gtaggaggct
tggtaggttt aagaatagtt 2940tttgctgtac tttctatagt gaatagagtt aggcagggat
attcaccatt atcgtttcag 3000acccacctcc caaccccgag gggacccgac aggcccgaag
gaatagaaga agaaggtgga 3060gagagagaca gagacagatc cattcgatta gtgaacggat
ccttggcact tatctgggac 3120gatctgcgga gcctgtgcct cttcagctac caccgcttga
gagacttact cttgattgta 3180acgaggattg tggaacttct gggacgcagg gggtgggaag
ccctcaaata ttggtggaat 3240ctcctacagt attggagtca ggaactaaag aatagtgctg
ttagcttgct caatgccaca 3300gccatagcag tagctgaggg gacagatagg gttatagaag
tagtacaagg agcttgtaga 3360gctattcgcc acatacctag aagaataaga cagggcttgg
aaaggatttt gctataa 3417192133DNAArtificial SequenceChimeric
sequences 19atgaaggcaa tactagtagt tctgctatat acatttgcaa ccgcaaatgc
agacacatta 60tgtataggtg gttatcatgc gaacaattca acagacactg tagacacagt
actagaaaag 120aatgtaacag taacacactc tgttaacctt ctagaagaca agcataacgg
gaaactatgc 180aaactaagag gggtagcccc attgcatttg ggtaaatgta acattgctgg
ctggatcctg 240ggaaatccag agtgtgaatc actctccaca gcaagctcat ggtcctacat
tgtggaaaca 300cctagttcag acaatggaac gtgttaccca ggagatttca tcgattatga
ggagctaaga 360gagcaattga gctcagtgtc atcatttgaa aggtttgaga tattccccaa
gacaagttca 420tggcccaatc atgactcgaa caaaggtgta acggcagcat gtcctcatgc
tggagcaaaa 480agcttctaca aaaatttaat atggctagtt aaaaaaggaa attcataccc
aaagctcagc 540aaatcctaca ttaatgataa agggaaagaa gtcctcgtgc tatggggcat
tcaccatcca 600tctactagtg ctgaccaaca aagtctctat cagaatgcag atgcatatgt
ttttgtgggg 660tcatcaagat acagcaagaa gttcaagccg gaaatagcaa taagacccaa
agtgagggrt 720cragaaggga gaatgaacta ttactggaca ctagtagagc cgggagacaa
aataacattc 780gaagcaactg gaaatctagt ggtaccgaga tatgcattcg caatggaaag
aaatgctgga 840tctggtatta tcatttcaga tacaccagtc cacgattgca atacaacttg
tcaaacaccc 900aagggtgcta taaacaccag cctcccattt cagaatatac atccgatcac
aattggaaaa 960tgtccaaaat atgtaaaaag cacaaaattg agactggcca caggattgag
gaatatcccg 1020tctattcaat ctagaggcct atttggggcc attgccggtt tcattgaagg
ggggtggaca 1080gggatggtag atggatggta cggttatcac catcaaaatg agcaggggtc
aggatatgca 1140gccgacctga agagcacaca gaatgccatt gacgagatta ctaacaaagt
aaattctgtt 1200attgaaaaga tgaatacaca gttcacagca gtaggtaaag agttcaacca
cctggaaaaa 1260agaatagaga atttaaataa aaaagttgat gatggtttcc tggacatttg
gacttacaat 1320gccgaactgt tggttctatt ggaaaatgaa agaactttgg actaccacga
ttcaaatgtg 1380aagaacttat atgaaaaggt aagaagccag ctaaaaaaca atgccaagga
aattggaaac 1440ggctgctttg aattttacca caaatgcgat aacacgtgca tggaaagtgt
caaaaatggg 1500acttatgact acccaaaata ctcagaggaa gcaaaattaa acagagaaga
aatagatggg 1560gtaaagctgg aatcaacaag gggtgatgct gcagcagatg gttatataaa
attattcata 1620atgatagtag gaggcttggt aggtttaaga atagtttttg ctgtactttc
tatagtgaat 1680agagttaggc agggatattc accattatcg tttcagaccc acctcccaac
cccgagggga 1740cccgacaggc ccgaaggaat agaagaagaa ggtggagaga gagacagaga
cagatccatt 1800cgattagtga acggatcctt ggcacttatc tgggacgatc tgcggagcct
gtgcctcttc 1860agctaccacc gcttgagaga cttactcttg attgtaacga ggattgtgga
acttctggga 1920cgcagggggt gggaagccct caaatattgg tggaatctcc tacagtattg
gagtcaggaa 1980ctaaagaata gtgctgttag cttgctcaat gccacagcca tagcagtagc
tgaggggaca 2040gatagggtta tagaagtagt acaaggagct tgtagagcta ttcgccacat
acctagaaga 2100ataagacagg gcttggaaag gattttgcta taa
2133201714DNAArtificial SequenceChimeric sequences
20atgggtgcga gagcgtcagt attaagcggg ggagaattag atcgatggga aaaaattcgg
60ttaaggccag ggggaaagaa aaaatataaa ttaaaacata tagtatgggc aagcagggag
120ctagaacgat tcgcagttaa tcctggcctg ttagaaacat cagaaggctg tagacaaata
180ctgggacagc tacaaccatc ccttcagaca ggatcagaag aacttagatc attatataat
240acagtagcaa ccctctattg tgtgcatcaa aggatagaga taaaagacac caaggaagct
300ttagacaaga tagaggaaga gcaaaacaaa agtaagaaaa aagcacagca agcagcagct
360gacacaggac acagcaatca ggtcagccaa aattacccta tagtgcagaa catccagggg
420caaatggtac atcaggccat atcacctaga actttaaatg catgggtaaa agtagtagaa
480gagaaggctt tcagcccaga agtgataccc atgttttcag cattatcaga aggagccacc
540ccacaagatt taaacaccat gctaaacaca gtggggggac atcaagcagc catgcaaatg
600ttaaaagaga ccatcaatga ggaagctgca gaatgggata gagtgcatcc agtgcatgca
660gggcctattg caccaggcca gatgagagaa ccaaggggaa gtgacatagc aggaactact
720agtacccttc aggaacaaat aggatggatg acaaataatc cacctatccc agtaggagaa
780atttataaaa gatggataat cctgggatta aataaaatag taagaatgta tagccctacc
840agcattctgg acataagaca aggaccaaag gaacccttta gagactatgt agaccggttc
900tataaaactc taagagccga gcaagcttca caggaggtaa aaaattggat gacagaaacc
960ttgttggtcc aaaatgcgaa cccagattgt aagactattt taaaagcatt gggaccagcg
1020gctacactag aagaaatgat gacagcatgt cagggagtag gaggacccgg ccataaggca
1080agagttttgg ctgaagcaat gagccaagta acaaattcag ctaccataat gatgcagaga
1140ggcaatttta ggatgaaaca acttgaagac aaggttgaag aattgctttc gaaaaattat
1200cacttggaaa atgaggttgc cagattaaag aaattagttg gcgaacgcag ggaagatctg
1260gccttcctac aagggaaggc cagggaattt tcttcagagc agaccagagc caacagcccc
1320accagaagag agcttcaggt ctggggtaga gacaacaact ccccctcaga agcaggagcc
1380gatagacaag gaactgtatc ctttaacttc cctcaggtca ctctttggca acgacccctc
1440gtcacaataa agataggggg gcaactaaag gaagctctat tagatacagg agcagatgat
1500acagtattag aagaaatgag tttgccagga agatggaaac caaaaatgat agggggaatt
1560ggaggtttta tcaaagtaag acagtatgat cagatactca tagaaatctg tggacataaa
1620gctataggta cagtattagt aggacctaca cctgtcaaca taattggaag aaatctgttg
1680actcagattg gttgcacttt aaattttccc atag
1714211248DNAArtificial SequenceChimeric sequences 21atgggtgcga
gagcgtcagt attaagcggg ggagaattag atcgatggga aaaaattcgg 60ttaaggccag
ggggaaagaa aaaatataaa ttaaaacata tagtatgggc aagcagggag 120ctagaacgat
tcgcagttaa tcctggcctg ttagaaacat cagaaggctg tagacaaata 180ctgggacagc
tacaaccatc ccttcagaca ggatcagaag aacttagatc attatataat 240acagtagcaa
ccctctattg tgtgcatcaa aggatagaga taaaagacac caaggaagct 300ttagacaaga
tagaggaaga gcaaaacaaa agtaagaaaa aagcacagca agcagcagct 360gacacaggac
acagcaatca ggtcagccaa aattacccta tagtgcagaa catccagggg 420caaatggtac
atcaggccat atcacctaga actttaaatg catgggtaaa agtagtagaa 480gagaaggctt
tcagcccaga agtgataccc atgttttcag cattatcaga aggagccacc 540ccacaagatt
taaacaccat gctaaacaca gtggggggac atcaagcagc catgcaaatg 600ttaaaagaga
ccatcaatga ggaagctgca gaatgggata gagtgcatcc agtgcatgca 660gggcctattg
caccaggcca gatgagagaa ccaaggggaa gtgacatagc aggaactact 720agtacccttc
aggaacaaat aggatggatg acaaataatc cacctatccc agtaggagaa 780atttataaaa
gatggataat cctgggatta aataaaatag taagaatgta tagccctacc 840agcattctgg
acataagaca aggaccaaag gaacccttta gagactatgt agaccggttc 900tataaaactc
taagagccga gcaagcttca caggaggtaa aaaattggat gacagaaacc 960ttgttggtcc
aaaatgcgaa cccagattgt aagactattt taaaagcatt gggaccagcg 1020gctacactag
aagaaatgat gacagcatgt cagggagtag gaggacccgg ccataaggca 1080agagttttgg
ctgaagcaat gagccaagta acaaattcag ctaccataat gatgcagaga 1140ggcaatttta
ggatgaaaca acttgaagac aaggttgaag aattgctttc gaaaaattat 1200cacttggaaa
atgaggttgc cagattaaag aaattagttg gcgaacgc
124822960DNAArtificial SequenceChimeric sequences 22atgaagacca tcattgcttt
gagctacatt ttctgtctgg ctctcggcgg gagatctgac 60aaaactcaca catgcccacc
gtgcccagca cctgaactcc tggcgggacc ggacgtcttc 120ctcttccccc caaaacccaa
ggacaccctc atgatctccc ggacccctga ggtcacatgc 180gtggtggtgg acgtgagcca
cgaagaccct gaggtcaagt tcaactggta cgtggacggc 240gtggaggtgc ataatgccaa
gacaaagccg cgggaggagc agtacaacag cacgtaccgt 300gtggtcagcg tcctcaccgt
cctgcaccag gactggctga atggcaagga gtacaagtgc 360aaggtctcca acaaagccct
cccagccccc gaggagaaaa ccatctccaa agccaaaggg 420cagccccgag aaccacaggt
gtacaccctg cccccatccc gggaggagat gaccaagaac 480caggtcagcc tgacctgcct
ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 540gagagcaatg ggcagccgga
gaacaactac aagaccacgc ctcccgtgct ggactccgac 600ggctccttct tcctctacag
caagctcacc gtggacaaga gcaggtggca gcaggggaac 660gtcttctcat gctccgtgat
gcacgaggct ctgcacaacc actacacgca gaagagcctc 720tccctgtctc cgggtaaagg
tgatgctgca gcagatggtg gattcctccc ttatgttatg 780cccctattag gccctttgct
ttgcttattg cttgtgttat ctttcggtcc aattattttc 840aacaagctta tgacctttat
taaacatcaa attgagagca tccaggccaa acctatacaa 900gtccattatc atcgccttga
acaagaagac agtggtggct catatttgac cttaacatag 960231782DNAArtificial
SequenceChimeric sequences 23atggccatca tttatctcat tctcctgttc acagcagtga
gagggaatga caacagcacg 60gcaacgctgt gccttgggca ccatgcagta ccaaacggaa
cgatagtgaa aacaatcacg 120aatgaccaaa ttgaagttac taatgctact gagctggttc
agagttcctc aacaggtgaa 180atatgcgaca gtcctcatca gatccttgat ggaaaaaact
gcacactaat agatgctcta 240ttgggagacc ctcagtgtga tggcttccaa aataagaaat
gggacctttt tgttgaacgc 300agcaaagcct acagcaactg ttacccttat gatgtgccgg
attatgcctc ccttaggtca 360ctagttgcct catccggcac actggagttt aacaatgaaa
gcttcaattg gactggagtc 420actcaaaacg gaacaagctc tgcttgcata aggagatcta
aaaacagttt ctttagtaga 480ttgaattggt tgacccactt aaacttcaaa tacccagcat
tgaacgtgac tatgccaaac 540aatgaacaat ttgacaaatt gtacatttgg ggggttcacc
acccgggtac ggacaaagac 600caaatcttcc tgtatgctca agcatcagga agaatcacag
tctctaccaa aagaagccaa 660caaaccgtaa gcccgaatat cggatctaga cccagagtaa
ggaatatccc tagcagaata 720agcatctatt ggacaatagt aaaaccggga gacatacttt
tgattaacag cacagggaat 780ctaattgctc ctaggggtta cttcaaaata cgaagtggga
aaagctcaat aatgagatca 840gatgcaccca ttggcaaatg caattctgaa tgcatcactc
caaatggaag cattcccaat 900gacaaaccat tccaaaatgt aaacaggatc acatacgggg
cctgtcccag atatgttaag 960caaaacactc tgaaattggc aacagggatg cgaaatgtac
cagagaaaca aactagaggc 1020atatttggcg caatcgcggg tttcatagaa aatggttggg
agggaatggt ggatggttgg 1080tacggtttca ggcatcaaaa ttctgaggga agaggacaag
cagcagatct caaaagcact 1140caagcagcaa tcgatcaaat caatgggaag ctgaatagat
tgatcgggaa aaccaacgag 1200aaattccatc agattgaaaa agaattctca gaagtcgaag
ggagaattca ggaccttgag 1260aaatatgttg aggacactaa aatagatctc tggtcataca
acgcggagct tcttgttgcc 1320ctggagaacc aacatacaat tgatctaact gactcagaaa
tgaacaaact gtttgaaaaa 1380acaaagaagc aactgaggga aaatgctgag gatatgggca
atggttgttt caaaatatac 1440cacaaatgtg acaatgcctg cataggatca atcagaaatg
gaacttatga ccacgatgta 1500tacagagatg aagcattaaa caaccggttt cagatcaagg
gagttgagct gaagtcaggg 1560ggtgatgctg cagcagatgg tggattcctc ccttatgtta
tgcccctatt aggccctttg 1620ctttgcttat tgcttgtgtt atctttcggt ccaattattt
tcaacaagct tatgaccttt 1680attaaacatc aaattgagag catccaggcc aaacctatac
aagtccatta tcatcgcctt 1740gaacaagaag acagtggtgg ctcatatttg accttaacat
ag 1782241752DNAArtificial SequenceChimeric
sequences 24atggggcaag aattaagcca gcatgaacgt tatgtagaac aattgaagca
ggctttaaag 60acacggggag taaaggttaa atatgctgat cttttgaaat tttttgattt
tgtgaaggat 120acttgtcctt ggtttccgca agagggaacc atagatatta aacggtggcg
tagagtaggc 180gactgtttcc aagactatta caatactttt ggcccggaga aagtcccagt
aactgcattc 240tcttactgga acttaattaa agaattgata gataagaaag aagttaaccc
acaagtaatg 300gctgccgtag cccaaactga agaaatttta aaaagtaatt ctcaaacaga
cctcacaaag 360acctctcaaa acccagactt ggaccttatt tcccttgata gcgacgatga
aggagctaaa 420agttcctctc tacaagataa aggtttatca agtactaaaa aaccaaaaag
attcccagtt 480ctgttaacag cacaaactag taaagaccct gaagacccca acccctcaga
ggtagactgg 540gacggcttgg aagatgaggc agcgaaatat cataatcccg attggcctcc
cttcctaacc 600cgtccacctc cttacaataa agctactcct tccgcaccca ctgtaatggc
ggttgttaat 660ccaaaagagg agctcaaaga aaaaattgct caattagagg aacagattaa
attagaagag 720ttacaccagg cactaatttc caaattacaa aaactaaaaa cagggaatga
aactgtaact 780cacccagaca cagcaggagg cctttctcgc acgcctcact ggccagggca
acatatccct 840aaaggaaaat gttgcgccag tcgagaaaag gaagaacaaa tcccaaaaga
tattttccca 900gtgactgaaa ccgttgatgg gcaaggtcaa gcctggagac accataatgg
ttttgatttt 960gccgtcataa aagaattaaa aacagctgct tcccaatatg gggctactgc
cccatacaca 1020ttagccatag tggaatctgt agcggacaat tggcttaccc ctacagattg
gaatacgctt 1080gttagggcag tcctctcagg aggagatcac ttactgtgga aatctgagtt
ttttgaaaat 1140tgcagagata cggctaaaag aaaccaacaa gccggtaatg gctgggattt
tgacatgtta 1200acaggttcgg gtaattattc cagcaccgat gcacaaatgc agtatgatcc
aggattgttt 1260gctcaaattc aagcggctgc tacaaaagcc tggagaaaac ttcccgttaa
gggagaccca 1320ggagcctccc ttacaggagt caaacaagga cccgatgagc catttgcaga
tttcgtacac 1380agacttataa caactgctgg gagaatcttt ggaagtgctg aggccggtgt
agactatgta 1440aaacaactag catatgaaaa tgctaatcca gcttgtcagg cagccattcg
cccctataga 1500aagaagacag atttaactgg ctatatccgt ctttgctcgg atattgggcc
ctcttatcag 1560caaggcctgg ccatggccgc cgcctttagc gggcagactg taaaagattt
tcttaacaac 1620aaaaataaag agaaaggagg gggtgctgca ggtatgaaac aacttgaaga
caaggttgaa 1680gaattgcttt cgaaaaatta tcacttggaa aatgaggttg ccagattaaa
gaaattagtt 1740ggcgaacgct ag
1752252661DNAArtificial SequenceChimeric sequences
25atggggcaag aattaagcca gcatgaacgt tatgtagaac aattgaagca ggctttaaag
60acacggggag taaaggttaa atatgctgat cttttgaaat tttttgattt tgtgaaggat
120acttgtcctt ggtttccgca agagggaacc atagatatta aacggtggcg tagagtaggc
180gactgtttcc aagactatta caatactttt ggcccggaga aagtcccagt aactgcattc
240tcttactgga acttaattaa agaattgata gataagaaag aagttaaccc acaagtaatg
300gctgccgtag cccaaactga agaaatttta aaaagtaatt ctcaaacaga cctcacaaag
360acctctcaaa acccagactt ggaccttatt tcccttgata gcgacgatga aggagctaaa
420agttcctctc tacaagataa aggtttatca agtactaaaa aaccaaaaag attcccagtt
480ctgttaacag cacaaactag taaagaccct gaagacccca acccctcaga ggtagactgg
540gacggcttgg aagatgaggc agcgaaatat cataatcccg attggcctcc cttcctaacc
600cgtccacctc cttacaataa agctactcct tccgcaccca ctgtaatggc ggttgttaat
660ccaaaagagg agctcaaaga aaaaattgct caattagagg aacagattaa attagaagag
720ttacaccagg cactaatttc caaattacaa aaactaaaaa cagggaatga aactgtaact
780cacccagaca cagcaggagg cctttctcgc acgcctcact ggccagggca acatatccct
840aaaggaaaat gttgcgccag tcgagaaaag gaagaacaaa tcccaaaaga tattttccca
900gtgactgaaa ccgttgatgg gcaaggtcaa gcctggagac accataatgg ttttgatttt
960gccgtcataa aagaattaaa aacagctgct tcccaatatg gggctactgc cccatacaca
1020ttagccatag tggaatctgt agcggacaat tggcttaccc ctacagattg gaatacgctt
1080gttagggcag tcctctcagg aggagatcac ttactgtgga aatctgagtt ttttgaaaat
1140tgcagagata cggctaaaag aaaccaacaa gccggtaatg gctgggattt tgacatgtta
1200acaggttcgg gtaattattc cagcaccgat gcacaaatgc agtatgatcc aggattgttt
1260gctcaaattc aagcggctgc tacaaaagcc tggagaaaac ttcccgttaa gggagaccca
1320ggagcctccc ttacaggagt caaacaagga cccgatgagc catttgcaga tttcgtacac
1380agacttataa caactgctgg gagaatcttt ggaagtgctg aggccggtgt agactatgta
1440aaacaactag catatgaaaa tgctaatcca gcttgtcagg cagccattcg cccctataga
1500aagaagacag atttaactgg ctatatccgt ctttgctcgg atattgggcc ctcttatcag
1560caaggcctgg ccatggccgc cgcctttagc gggcagactg taaaagattt tcttaacaac
1620aaaaataaag agaaaggagg gggtgctgca ggtatgaaac aacttgaaga caaggttgaa
1680gaattgcttt cgaaaaatta tcacttggaa aatgaggttg ccagattaaa gaaattagtt
1740ggcgaacgca gggtggaggg gccagcccca ggccccgaaa caagcttatg gggcagtcag
1800ctttgttcca gccaacaaaa acaacccatt tcaaagctta ccagagccac cccaggaagt
1860gcaggattgg acctctgttc cacctcccac acagtattaa cgcctgaaat ggggccccaa
1920gcgttaagca ctggaatata tggaccactg cctcccaaca cttttggatt aatcctaggc
1980cgaagtagca ttactatgaa gggtctacaa gtttatccag gagtaattga taatgactat
2040accggagaaa ttaaaattat ggcaaaagct gttaacaata ttgttactgt ctctcaaggc
2100aacagaatag ctcaattaat cctcctgcct ctgatcgaga cagacaataa ggtacaacaa
2160ccttatagag gacaaggaag ttttggatcc tcagacatat attgggtcca acctattact
2220tgtcaaaaac cttccttaac attatggtta gatgacaaaa tgttcacagg cttaatagat
2280acgggggctg atgtcacaat tatcaagctg gaggactggc ctcctaattg gcctataaca
2340gataccttaa ccaatttaag aggaatagga caaagtaaca accctaaaca aagttctaaa
2400tatcttactt ggagagataa agaaaacaat tctggtctca tcaaaccgtt tgttattcct
2460aacttacctg tcaatctttg gggccgagat ttactttctc aaatgaaaat tatgatgtgt
2520agccccaatg acatagtaac tgctcaaatg ttagcccagg gctacagccc aggaaaaggg
2580ttaggaaaaa aggaaaatgg cattctacat cctatcccaa atcaaggaca atctaacaaa
2640aaaggttttg gaaattttta a
2661263219DNAArtificial SequenceChimeric sequences 26atggggcaag
aattaagcca gcatgaacgt tatgtagaac aattgaagca ggctttaaag 60acacggggag
taaaggttaa atatgctgat cttttgaaat tttttgattt tgtgaaggat 120acttgtcctt
ggtttccgca agagggaacc atagatatta aacggtggcg tagagtaggc 180gactgtttcc
aagactatta caatactttt ggcccggaga aagtcccagt aactgcattc 240tcttactgga
acttaattaa agaattgata gataagaaag aagttaaccc acaagtaatg 300gctgccgtag
cccaaactga agaaatttta aaaagtaatt ctcaaacaga cctcacaaag 360acctctcaaa
acccagactt ggaccttatt tcccttgata gcgacgatga aggagctaaa 420agttcctctc
tacaagataa aggtttatca agtactaaaa aaccaaaaag attcccagtt 480ctgttaacag
cacaaactag taaagaccct gaagacccca acccctcaga ggtagactgg 540gacggcttgg
aagatgaggc agcgaaatat cataatcccg attggcctcc cttcctaacc 600cgtccacctc
cttacaataa agctactcct tccgcaccca ctgtaatggc ggttgttaat 660ccaaaagagg
agctcaaaga aaaaattgct caattagagg aacagattaa attagaagag 720ttacaccagg
cactaatttc caaattacaa aaactaaaaa cagggaatga aactgtaact 780cacccagaca
cagcaggagg cctttctcgc acgcctcact ggccagggca acatatccct 840aaaggaaaat
gttgcgccag tcgagaaaag gaagaacaaa tcccaaaaga tattttccca 900gtgactgaaa
ccgttgatgg gcaaggtcaa gcctggagac accataatgg ttttgatttt 960gccgtcataa
aagaattaaa aacagctgct tcccaatatg gggctactgc cccatacaca 1020ttagccatag
tggaatctgt agcggacaat tggcttaccc ctacagattg gaatacgctt 1080gttagggcag
tcctctcagg aggagatcac ttactgtgga aatctgagtt ttttgaaaat 1140tgcagagata
cggctaaaag aaaccaacaa gccggtaatg gctgggattt tgacatgtta 1200acaggttcgg
gtaattattc cagcaccgat gcacaaatgc agtatgatcc aggattgttt 1260gctcaaattc
aagcggctgc tacaaaagcc tggagaaaac ttcccgttaa gggagaccca 1320ggagcctccc
ttacaggagt caaacaagga cccgatgagc catttgcaga tttcgtacac 1380agacttataa
caactgctgg gagaatcttt ggaagtgctg aggccggtgt agactatgta 1440aaacaactag
catatgaaaa tgctaatcca gcttgtcagg cagccattcg cccctataga 1500aagaagacag
atttaactgg ctatatccgt ctttgctcgg atattgggcc ctcttatcag 1560caaggcctgg
ccatggccgc cgcctttagc gggcagactg taaaagattt tcttaacaac 1620aaaaataaag
agaaaggagg gggtgctgca ggtatgaaac aacttgaaga caaggttgaa 1680gaattgcttt
cgaaaaatta tcacttggaa aatgaggttg ccagattaaa gaaattagtt 1740ggcgaacgct
ttcttaacaa caaaaataaa gagggagggg gtgctgcaac catggttgac 1800acagagatgc
cattctggcc caccaacttt gggatcagct ccgtggatct ctccgtaatg 1860gaagaccact
cccactcctt tgatatcaag cccttcacta ctgttgactt ctccagcatt 1920tctactccac
attacgaaga cattccattc acaagaacag atccagtggt tgcagattac 1980aagtatgacc
tgaaacttca agagtaccaa agtgcaatca aagtggagcc tgcatctcca 2040ccttattatt
ctgagaagac tcagctctac aataagcctc atgaagagcc ttccaactcc 2100ctcatggcaa
ttgaatgtcg tgtctgtgga gataaagctt ctggatttca ctatggagtt 2160catgcttgtg
aaggatgcaa gggtttcttc cggagaacaa tcagattgaa gcttatctat 2220gacagatgtg
atcttaactg tcggatccac aaaaaaagta gaaataaatg tcagtactgt 2280cggtttcaga
aatgccttgc agtggggatg tctcataatg ccatcaggtt tgggcggatg 2340ccacaggccg
agaaggagaa gctgttggcg gagatctcca gtgatatcga ccagctgaat 2400ccagagtccg
ctgacctccg ggccctggca aaacatttgt atgactcata cataaagtcc 2460ttcccgctga
ccaaagcaaa ggcgagggcg atcttgacag gaaagacaac agacaaatca 2520ccattcgtta
tctatgacat gaattcctta atgatgggag aagataaaat caagttcaaa 2580cacatcaccc
ccctgcagga gcagagcaaa gaggtggcca tccgcatctt tcagggctgc 2640cagtttcgct
ccgtggaggc tgtgcaggag atcacagagt atgccaaaag cattcctggt 2700tttgtaaatc
ttgacttgaa cgaccaagta actctcctca aatatggagt ccacgagatc 2760atttacacaa
tgctggcctc cttgatgaat aaagatgggg ttctcatatc cgagggccaa 2820ggcttcatga
caagggagtt tctaaagagc ctgcgaaagc cttttggtga ctttatggag 2880cccaagtttg
agtttgctgt gaagttcaat gcactggaat tagatgacag cgacttggca 2940atatttattg
ctgtcattat tctcagtgga gaccgcccag gtttgctgaa tgtgaagccc 3000attgaagaca
ttcaagacaa cctgctacaa gccctggagc tccagctgaa gctgaaccac 3060cctgagtcct
cacagctgtt tgccaagctg ctccagaaaa tgacagacct cagacagatt 3120gtcacggaac
acgtgcagct actgcaggtg atcaagaaga cggagacaga catgagtctt 3180cacccgctcc
tgcaggagat ctacaaggac ttgtactag
3219273129DNAArtificial SequenceChimeric sequences 27atggggcaag
aattaagcca gcatgaacgt tatgtagaac aattgaagca ggctttaaag 60acacggggag
taaaggttaa atatgctgat cttttgaaat tttttgattt tgtgaaggat 120acttgtcctt
ggtttccgca agagggaacc atagatatta aacggtggcg tagagtaggc 180gactgtttcc
aagactatta caatactttt ggcccggaga aagtcccagt aactgcattc 240tcttactgga
acttaattaa agaattgata gataagaaag aagttaaccc acaagtaatg 300gctgccgtag
cccaaactga agaaatttta aaaagtaatt ctcaaacaga cctcacaaag 360acctctcaaa
acccagactt ggaccttatt tcccttgata gcgacgatga aggagctaaa 420agttcctctc
tacaagataa aggtttatca agtactaaaa aaccaaaaag attcccagtt 480ctgttaacag
cacaaactag taaagaccct gaagacccca acccctcaga ggtagactgg 540gacggcttgg
aagatgaggc agcgaaatat cataatcccg attggcctcc cttcctaacc 600cgtccacctc
cttacaataa agctactcct tccgcaccca ctgtaatggc ggttgttaat 660ccaaaagagg
agctcaaaga aaaaattgct caattagagg aacagattaa attagaagag 720ttacaccagg
cactaatttc caaattacaa aaactaaaaa cagggaatga aactgtaact 780cacccagaca
cagcaggagg cctttctcgc acgcctcact ggccagggca acatatccct 840aaaggaaaat
gttgcgccag tcgagaaaag gaagaacaaa tcccaaaaga tattttccca 900gtgactgaaa
ccgttgatgg gcaaggtcaa gcctggagac accataatgg ttttgatttt 960gccgtcataa
aagaattaaa aacagctgct tcccaatatg gggctactgc cccatacaca 1020ttagccatag
tggaatctgt agcggacaat tggcttaccc ctacagattg gaatacgctt 1080gttagggcag
tcctctcagg aggagatcac ttactgtgga aatctgagtt ttttgaaaat 1140tgcagagata
cggctaaaag aaaccaacaa gccggtaatg gctgggattt tgacatgtta 1200acaggttcgg
gtaattattc cagcaccgat gcacaaatgc agtatgatcc aggattgttt 1260gctcaaattc
aagcggctgc tacaaaagcc tggagaaaac ttcccgttaa gggagaccca 1320ggagcctccc
ttacaggagt caaacaagga cccgatgagc catttgcaga tttcgtacac 1380agacttataa
caactgctgg gagaatcttt ggaagtgctg aggccggtgt agactatgta 1440aaacaactag
catatgaaaa tgctaatcca gcttgtcagg cagccattcg cccctataga 1500aagaagacag
atttaactgg ctatatccgt ctttgctcgg atattgggcc ctcttatcag 1560caaggcctgg
ccatggccgc cgcctttagc gggcagactg taaaagattt tcttaacaac 1620aaaaataaag
agaaaggagg gggtgctgca ggtatgaaac aacttgaaga caaggttgaa 1680gaattgcttt
cgaaaaatta tcacttggaa aatgaggttg ccagattaaa gaaattagtt 1740ggcgaacgct
ttcttaacaa caaaaataaa gagggagggg gtgctgcatc cttgtggctg 1800ggggcccctg
tgcctgacat tcctcctgac tctgcggtgg agctgtggaa gccaggcgca 1860caggatgcaa
gcagccaggc ccagggaggc agcagctgca tcctcagaga ggaagccagg 1920atgccccact
ctgctggggg tactgcaggg gtggggctgg aggctgcaga gcccacagcc 1980ctgctcacca
gggcagagcc cccttcagaa cccacagaga tccgtccaca aaagcggaaa 2040aaggggccag
cccccaaaat gctggggaac gagctatgca gcgtgtgtgg ggacaaggcc 2100tcgggcttcc
actacaatgt tctgagctgc gagggctgca agggattctt ccgccgcagc 2160gtcatcaagg
gagcgcacta catctgccac agtggcggcc actgccccat ggacacctac 2220atgcgtcgca
agtgccagga gtgtcggctt cgcaaatgcc gtcaggctgg catgcgggag 2280gagtgtgtcc
tgtcagaaga acagatccgc ctgaagaaac tgaagcggca agaggaggaa 2340caggctcatg
ccacatcctt gccccccagg gcttcctcac ccccccaaat cctgccccag 2400ctcagcccgg
aacaactggg catgatcgag aagctcgtcg ctgcccagca acagtgtaac 2460cggcgctcct
tttctgaccg gcttcgagtc acgccttggc ccatggcacc agatccccat 2520agccgggagg
cccgtcagca gcgctttgcc cacttcactg agctggccat cgtctctgtg 2580caggagatag
ttgactttgc taaacagcta cccggcttcc tgcagctcag ccgggaggac 2640cagattgccc
tgctgaagac ctctgcgatc gaggtgatgc ttctggagac atctcggagg 2700tacaaccctg
ggagtgagag tatcaccttc ctcaaggatt tcagttataa ccgggaagac 2760tttgccaaag
cagggctgca agtggaattc atcaacccca tcttcgagtt ctccagggcc 2820atgaatgagc
tgcaactcaa tgatgccgag tttgccttgc tcattgctat cagcatcttc 2880tctgcagacc
ggcccaacgt gcaggaccag ctccaggtag agaggctgca gcacacatat 2940gtggaagccc
tgcatgccta cgtctccatc caccatcccc atgaccgact gatgttccca 3000cggatgctaa
tgaaactggt gagcctccgg accctgagca gcgtccactc agagcaagtg 3060tttgcactgc
gtctgcagga caaaaagctc ccaccgctgc tctctgagat ctgggatgtg 3120cacgaatga
3129284020DNAArtificial SequenceChimeric sequences 28atggggcaag
aattaagcca gcatgaacgt tatgtagaac aattgaagca ggctttaaag 60acacggggag
taaaggttaa atatgctgat cttttgaaat tttttgattt tgtgaaggat 120acttgtcctt
ggtttccgca agagggaacc atagatatta aacggtggcg tagagtaggc 180gactgtttcc
aagactatta caatactttt ggcccggaga aagtcccagt aactgcattc 240tcttactgga
acttaattaa agaattgata gataagaaag aagttaaccc acaagtaatg 300gctgccgtag
cccaaactga agaaatttta aaaagtaatt ctcaaacaga cctcacaaag 360acctctcaaa
acccagactt ggaccttatt tcccttgata gcgacgatga aggagctaaa 420agttcctctc
tacaagataa aggtttatca agtactaaaa aaccaaaaag attcccagtt 480ctgttaacag
cacaaactag taaagaccct gaagacccca acccctcaga ggtagactgg 540gacggcttgg
aagatgaggc agcgaaatat cataatcccg attggcctcc cttcctaacc 600cgtccacctc
cttacaataa agctactcct tccgcaccca ctgtaatggc ggttgttaat 660ccaaaagagg
agctcaaaga aaaaattgct caattagagg aacagattaa attagaagag 720ttacaccagg
cactaatttc caaattacaa aaactaaaaa cagggaatga aactgtaact 780cacccagaca
cagcaggagg cctttctcgc acgcctcact ggccagggca acatatccct 840aaaggaaaat
gttgcgccag tcgagaaaag gaagaacaaa tcccaaaaga tattttccca 900gtgactgaaa
ccgttgatgg gcaaggtcaa gcctggagac accataatgg ttttgatttt 960gccgtcataa
aagaattaaa aacagctgct tcccaatatg gggctactgc cccatacaca 1020ttagccatag
tggaatctgt agcggacaat tggcttaccc ctacagattg gaatacgctt 1080gttagggcag
tcctctcagg aggagatcac ttactgtgga aatctgagtt ttttgaaaat 1140tgcagagata
cggctaaaag aaaccaacaa gccggtaatg gctgggattt tgacatgtta 1200acaggttcgg
gtaattattc cagcaccgat gcacaaatgc agtatgatcc aggattgttt 1260gctcaaattc
aagcggctgc tacaaaagcc tggagaaaac ttcccgttaa gggagaccca 1320ggagcctccc
ttacaggagt caaacaagga cccgatgagc catttgcaga tttcgtacac 1380agacttataa
caactgctgg gagaatcttt ggaagtgctg aggccggtgt agactatgta 1440aaacaactag
catatgaaaa tgctaatcca gcttgtcagg cagccattcg cccctataga 1500aagaagacag
atttaactgg ctatatccgt ctttgctcgg atattgggcc ctcttatcag 1560caaggcctgg
ccatggccgc cgcctttagc gggcagactg taaaagattt tcttaacaac 1620aaaaataaag
agaaaggagg gggtgctgca ggtcgagagt gtcgtagaaa gaagaaagaa 1680tatgtgaaat
gtttagaaaa cagagtggca gtgcttgaaa atcaaaacaa gacattgatt 1740gaggagctaa
aagcacttaa ggacctttac tgccacaaat cagattttct taacaacaaa 1800aataaagagg
gagggggtgc tgcaacggag ggcacgtgtc tgcggcgccg agggggcccc 1860tacaagaccg
agcccgccac cgacctcggc cgctggcgac tcaactgcga gaggggccgg 1920cagacgtgga
cctacctgca ggacgagcgc gccggccgcg agcagaccgg cctggaagcc 1980tacgccctgg
ggctggacac caagaattac tttaaggact tgcccaaagc ccacaccgcc 2040tttgaggggg
ctctgaacgg gatgacattt tacgtggggc tgcaggctga ggatgggcac 2100tggacgggtg
attatggtgg cccacttttc ctcctgccag gcctcctgat cacttgccac 2160gtggcacgca
tccctctgcc agccggatac agagaagaga ttgtgcggta cctgcggtca 2220gtgcagctcc
ctgacggtgg ctggggcctg cacattgagg ataagtccac cgtgtttggg 2280actgcgctca
actatgtgtc tctcagaatt ctgggtgttg ggcctgacga tcctgacctg 2340gtacgagccc
ggaacattct tcacaagaaa ggtggtgctg tggccatccc ctcctggggg 2400aagttctggc
tggctgtcct gaatgtttac agctgggaag gcctcaatac cctgttccca 2460gagatgtggc
tgtttcctga ctgggcaccg gcacacccct ccacactctg gtgccactgc 2520cggcaggtgt
acctgcccat gagctactgc tacgccgttc ggctgagtgc cgcggaagac 2580ccgctggtcc
agagcctccg ccaggagctc tatgtggagg acttcgccag cattgactgg 2640ctggcgcaga
ggaacaacgt ggcccccgac gagctgtaca cgccccacag ctggctgctc 2700cgcgtggtat
atgcgctcct caacctgtat gagcaccacc acagtgccca cctgcggcag 2760cgggccgtgc
agaagctgta tgaacacatt gtggccgacg accgattcac caagagcatc 2820agcatcggcc
cgatctcgaa aaccatcaac atgcttgtgc gctggtatgt ggacgggccc 2880gcctccactg
ccttccagga gcatgtctcc agaatcccgg actatctctg gatgggcctt 2940gacggcatga
aaatgcaggg caccaacggc tcacagatct gggacaccgc attcgccatc 3000caggctctgc
ttgaggcggg cgggcaccac aggcccgagt tttcgtcctg cctgcagaag 3060gctcatgagt
tcctgaggct ctcacaggtc ccagataacc ctcccgacta ccagaagtac 3120taccgccaga
tgcgcaaggg tggcttctcc ttcagtacgc tggactgcgg ctggatcgtt 3180tctgactgca
cggctgaggc cttgaaggct gtgctgctcc tgcaggagaa gtgtccccat 3240gtcaccgagc
acatccccag agaacggctc tgcgatgctg tggctgtgct gctgaacatg 3300agaaatccag
atggagggtt cgccacctat gagaccaagc gtggggggca cttgctggag 3360ctgctgaacc
cctcggaggt cttcggggac atcatgattg actacaccta tgtggagtgc 3420acctcagccg
tgatgcaggc gcttaagtat ttccacaagc gtttcccgga gcacagggca 3480gcggagatcc
gggagaccct cacgcagggc ttagagttct gtcggcggca gcagagggcc 3540gatggctcct
gggaaggctc ctggggagtt tgcttcacct acggcacctg gtttggcctg 3600gaggccttcg
cctgtatggg gcagacctac cgagatggga ctgcctgtgc agaggtctcc 3660cgggcctgtg
acttcctgct gtcccggcag atggcagacg gaggctgggg ggaggacttt 3720gagtcctgcg
aggagcggcg ttatttgcag agtgcccagt cccagatcca taacacatgc 3780tgggccatga
tggggctgat ggccgttcgg catcctgaca tcgaggccca ggagagagga 3840gtccggtgtc
tacttgagaa acagctcccc aatggcgact ggccgcagga aaacattgct 3900ggggtcttca
acaagtcctg tgccatctcc tacacgagct acaggaacat cttccccatc 3960tgggccctcg
gccgcttctc ccagctgtac cctgagagag cccttgctgg ccacccctga
4020292214DNAArtificial SequenceChimeric sequences 29atgaagacca
tcattgcttt gagctacatt ttctgtctgg ctctcgctca aaaacttcct 60ggaagtccca
tgtactctat catcaccccc aacatcttgc ggctggagag cgaggagacc 120atggtgctgg
aggcccacga cgcgcaaggg gatgttccag tcactgttac tgtccacgac 180ttcccaggca
aaaaactagt gctgtccagt gagaagactg tgctgacccc tgccaccaac 240cacatgggca
acgtcacctt cacgatccca gccaacaggg agttcaagtc agaaaagggg 300cgcaacaagt
tcgtgaccgt gcaggccacc ttcgggaccc aagtggtgga gaaggtggtg 360ctggtcagcc
tgcagagcgg gtacctcttc atccagacag acaagaccat ctacacccct 420ggctccacag
ttctctatcg gatcttcacc gtcaaccaca agctgctacc cgtgggccgg 480acggtcatgg
tcaacattga gaacccggaa ggcatcccgg tcaagcagga ctccttgtct 540tctcagaacc
agcttggcgt cttgcccttg tcttgggaca ttccggaact cgtcaacatg 600ggccagtgga
agatccgagc ctactatgaa aactcaccac agcaggtctt ctccactgag 660tttgaggtga
aggagtacgt gctgcccagt ttcgaggtca tagtggagcc tacagagaaa 720ttctactaca
tctataacga gaagggcctg gaggtcacca tcaccgccag gttcctctac 780gggaagaaag
tggagggaac tgcctttgtc atcttcggga tccaggatgg cgaacagagg 840atttccctgc
ctgaatccct caagcgcatt ccgattgagg atggctcggg ggaggttgtg 900ctgagccgga
aggtactgct ggacggggtg cagaacctcc gagcagaaga cctggtgggg 960aagtctttgt
acgtgtctgc caccgtcatc ttgcactcag gcagtgacat ggtgcaggca 1020gagcgcagcg
ggatccccat cgtgacctct ccctaccaga tccacttcac caagacaccc 1080aagtacttca
aaccaggaat gccctttgac ctcatggtgt tcgtgacgaa ccctgatggc 1140tctccagcct
accgagtccc cgtggcagtc cagggcgagg acactgtgca gtctctaacc 1200cagggagatg
gcgtggccaa actcagcatc aacacacacc ccagccagaa gcccttgagc 1260atcacggtgc
gcacgaagaa gcaggagctc tcggaggcag agcaggctac caggaccatg 1320caggctctgc
cctacagcac cgtgggcaac tccaacaatt acctgcatct ctcagtgcta 1380cgtacagagc
tcagacccgg ggagaccctc aacgtcaact tcctcctgcg aatggaccgc 1440gcccacgagg
ccaagatccg ctactacacc tacctgatca tgaacaaggg caggctgttg 1500aaggcgggac
gccaggtgcg agagcccggc caggacctgg tggtgctgcc cctgtccatc 1560accaccgact
tcatcccttc cttccgcctg gtggcgtact acacgctgat cggtgccagc 1620ggccagaggg
aggtggtggc cgactccgtg tgggtggacg tcaaggactc ctgcgtgggc 1680tcgctggtgg
taaaaagcgg ccagtcagaa gaccggcagc ctgtacctgg gcagcagatg 1740accctgaaga
tagagggtga ccacggggcc cgggtggtac tggtggccgt ggacaagggc 1800gtgttcgtgc
tgaataagaa gaacaaactg acgcagagta agatctggga cgtggtggag 1860aaggcagaca
tcggctgcac cccgggcagt gggaaggatt acgccggtgt cttctccgac 1920gcagggctga
ccttcacgag cagcagtggc cagcagaccg cccagagggc agaacttcag 1980tgcccgcagc
cagccgccgg tgatgctgca gcagatggtg ggatattcgg gggaataggg 2040gaatgggccg
ttcatctgct aaaaggactg cttttggggc ttgtagttat tttattgcta 2100ctggtgtgcc
tgccttgcct tttacaattt gtgtctagta gtattcgaaa gatgattaat 2160agttcaatca
actatcatac tgaatacagg aagatgcagg gcggagcagt ctag
2214301797DNAArtificial SequenceChimeric sequences 30atggaaagaa
tagtgattgc cctcgcaata atcagcattg tcaaaggtga ccaaatttgc 60attggttacc
atgcaaacaa ttcaacagag caggttgata caatcatgga aaagaatgtg 120acggtcacac
atgctcagaa tatactggaa aaagagcaca atgggaaact ttgcagtctt 180aaaggagtga
ggcccctcat tctgaaggat tgcagtgtag ctggatggct tcttggaaac 240ccaatgtgtg
atgaattcct gaatgtacca gaatggtcat acatcgtgga aaaagataat 300ccagtcaatg
gcctgtgcta tccaggagac ttcagcgact acgaagaact gaagcattta 360atgagcagca
caaaccattt tgagaaaatt cagataatcc ctaggagttc ttggtccaat 420catgatgcct
catcaggagt gagttcggca tgcccataca atggtagatc ttccttattc 480aggaatgtag
tgtggttgat caagaagaat aatgcgtacc caacagtaaa gaggacctat 540aacaacacca
atgtagaaga ccttttaata atatggggaa tacaccaccc taatgatgca 600gctgaacaaa
caaaactcta ccagaactcg aacacttatg tgtctgtagg aacatcaaca 660ctgaaccaga
gatcaatccc agaaatagcc actagaccca aagtgaacgg acaaagtgga 720agaatggaat
ttttctggac aatactgaag tcgaacgatg caatcagctt tgaaagtaat 780gggaatttta
tagctcctga atatgcgtac aaaattgcca agaaaggaga ttcagcaatc 840atgagaagtg
aattggagta tggtaactgt gacaccaaat gtcagactcc attgggtgct 900ataaattcca
gtatgccctt ccacaatgtt catcctctta ccattgggga gtgccccaag 960tatgtcaaat
cggacaaact ggtccttgca acaggactaa gaaacgtacc ccaaagagaa 1020acaagaggcc
tatttggtgc aatagcagga ttcatagaag gaggatggca aggaatggtt 1080gacgggtggt
acggatacca tcatagcaat gagcagggaa gtggatatgc tgcagacaaa 1140gaatctaccc
agaaagcaat cgatgggatc accaatagag taaactcaat cattgacaaa 1200atgaacactc
aattcgaagc cgttgggaaa gaattcaaca acctagaaag gagaatagaa 1260aatttgaata
agaaaatgga agatgggttt ttagatgtat ggacttacaa tgcagaactt 1320ctcgtgctca
tggaaaacga aagaactctg gatttccatg attcaaatgt caagaaccta 1380tacgataagg
tccgactcca gctgagagac aatgcaaaag aattgggcaa cggatgcttc 1440gaattctacc
acaagtgtga caatgaatgc atggaaagtg tgagaaatgg aacgtatgac 1500tatccgcaat
attcagaaga atcaagactg aacagagagg aaatagacgg agtcaaattg 1560gaatcaatgg
gcacctatca gggtgatgct gcagcagatg gtgggatatt cgggggaata 1620ggggaatggg
ccgttcatct gctaaaagga ctgcttttgg ggcttgtagt tattttattg 1680ctactggtgt
gcctgccttg ccttttacaa tttgtgtcta gtagtattcg aaagatgatt 1740aatagttcaa
tcaactatca tactgaatac aggaagatgc agggcggagc agtctag
1797311959DNAArtificial SequenceChimeric sequences 31atggaagccg
tcataaaggt gatttcgtcc gcgtgtaaaa cctattgcgg gaaaacctct 60ccttctaaga
aggaaatagg ggccatgttg tccctcttac aaaaggaagg gttgcttatg 120tctccctcag
acttatattc cccggggtcc tgggatccca ttaccgcggc gctatcccag 180cgggctatga
tacttgggaa atcgggagag ttaaaaacct ggggattggt tttgggggca 240ttgaaggcgg
ctcgagagga acaggttaca tctgagcaag caaagttttg gttgggatta 300gggggaggga
gggtctctcc cccaggtccg gagtgcatcg agaaaccagc aacggagcgg 360cgaatcgaca
aaggggagga agtgggagaa acaactgtgc agcgagatgc gaagatggcg 420ccggaggaaa
cggccacacc taaaaccgtt ggcacatcct gctatcattg cggaacagct 480attggctgta
attgcgccac agcctcggct cctcctcctc cttatgtggg gagtggtttg 540tatccttccc
tggcgggggt gggagagcag cagggccagg ggggtgacac acctccgggg 600gcggaacagt
caagggcgga gccagggcat gcgggtcagg ctcctgggcc ggccctgact 660gactgggcaa
gggtcaggga ggagcttgcg agtactggtc cgcccgtggt ggccatgcct 720gtagtgatta
agacagaggg acccgcttgg acccctctgg agccaaaatt gatcacaaga 780ctggctgata
cggtcaggac caagggctta cgatccccga ttactatggc agaagtggaa 840gcgcttatgt
cctccccgct gctgccgcat gacgtcacga atctaatgag agttatttta 900gggcctgccc
catatgcctt atggatggac gcttggggag tccaactcca gacagttata 960gcggcagcca
ctcgcgaccc ccgacaccca gcgaacggtc aagggcgggg ggaacggact 1020aatttgaatc
gcttaaaggg cttagctgat gggatggtgg gcaacccaca gggtcaggcc 1080gcattattaa
gaccggggga attggttgct attacggcgt cggctctcca ggcgtttaga 1140gaggttgccc
ggctggcgga acctgcaggt ccatgggcgg acatcatgca gggaccatct 1200gagtcctttg
ttgattttgc caatcggctt ataaaggcgg ttgaggggtc agatctcccg 1260ccttccgcgc
gggctccggt gatcattgac tgctttaggc agaagtcaca gccagatatt 1320cagcagctta
tacggacagc accctccacg ctgaccaccc caggagagat aattaaatat 1380gtgctagaca
ggcagaagac tgcccctctt acggatcaag gcatagccgc ggccatgtcg 1440tctgctatcc
agcccttaat tatggcaggt gctgcaggta tgaaacaact tgaagacaag 1500gttgaagaat
tgctttcgaa aaattatcac ttggaaaatg aggttgccag attaaagaaa 1560ttagttggcg
aacgcgccgt ctcgttagcg atgacaatgg aacataaaga tcgccccttg 1620gttagggtca
ttctgactaa cactgggagt catccggtca aacagcgttc ggtgtatatc 1680accgcgctgt
tggactctgg agcggacatc actattattt cagaggagga ttggcccacc 1740gattggccag
tgatggaggc cgcgaacccg cagatccatg ggataggagg gggaattccc 1800atgcgaaaat
ctcgtgacat gatagagttg ggggttatta accgagacgg gtctttggag 1860cgacccctgc
tcctcttccc cgcagtagct atggttagag ggagtatcct aggaagagat 1920tgtctgcagg
gcctagggct ccgcttgaca aatttatag
1959322015DNAArtificial SequenceChimeric sequences 32atggaagccg
tcataaaggt gatttcgtcc gcgtgtaaaa cctattgcgg gaaaacctct 60ccttctaaga
aggaaatagg ggccatgttg tccctcttac aaaaggaagg gttgcttatg 120tctccctcag
acttatattc cccggggtcc tgggatccca ttaccgcggc gctatcccag 180cgggctatga
tacttgggaa atcgggagag ttaaaaacct ggggattggt tttgggggca 240ttgaaggcgg
ctcgagagga acaggttaca tctgagcaag caaagttttg gttgggatta 300gggggaggga
gggtctctcc cccaggtccg gagtgcatcg agaaaccagc aacggagcgg 360cgaatcgaca
aaggggagga agtgggagaa acaactgtgc agcgagatgc gaagatggcg 420ccggaggaaa
cggccacacc taaaaccgtt ggcacatcct gctatcattg cggaacagct 480attggctgta
attgcgccac agcctcggct cctcctcctc cttatgtggg gagtggtttg 540tatccttccc
tggcgggggt gggagagcag cagggccagg ggggtgacac acctccgggg 600gcggaacagt
caagggcgga gccagggcat gcgggtcagg ctcctgggcc ggccctgact 660gactgggcaa
gggtcaggga ggagcttgcg agtactggtc cgcccgtggt ggccatgcct 720gtagtgatta
agacagaggg acccgcttgg acccctctgg agccaaaatt gatcacaaga 780ctggctgata
cggtcaggac caagggctta cgatccccga ttactatggc agaagtggaa 840gcgcttatgt
cctccccgct gctgccgcat gacgtcacga atctaatgag agttatttta 900gggcctgccc
catatgcctt atggatggac gcttggggag tccaactcca gacagttata 960gcggcagcca
ctcgcgaccc ccgacaccca gcgaacggtc aagggcgggg ggaacggact 1020aatttgaatc
gcttaaaggg cttagctgat gggatggtgg gcaacccaca gggtcaggcc 1080gcattattaa
gaccggggga attggttgct attacggcgt cggctctcca ggcgtttaga 1140gaggttgccc
ggctggcgga acctgcaggt ccatgggcgg acatcatgca gggaccatct 1200gagtcctttg
ttgattttgc caatcggctt ataaaggcgg ttgaggggtc agatctcccg 1260ccttccgcgc
gggctccggt gatcattgac tgctttaggc agaagtcaca gccagatatt 1320cagcagctta
tacggacagc accctccacg ctgaccaccc caggagagat aattaaatat 1380gtgctagaca
ggcagaagac tgcccctctt acggatcaag gcatagccgc ggccatgtcg 1440tctgctatcc
agcccttaat tatggcaggt gctgcaggtc gagagtgtcg tagaaagaag 1500aaagaatatg
tgaaatgttt agaaaacaga gtggcagtgc ttgaaaatca aaacaagaca 1560ttgattgagg
agctaaaagc acttaaggac ctttactgcc acaaatcaga tgccgtctcg 1620ttagcgatga
caatggaaca taaagatcgc cccttggtta gggtcattct gactaacact 1680gggagtcatc
cggtcaaaca gcgttcggtg tatatcaccg cgctgttgga ctctggagcg 1740gacatcacta
ttatttcaga ggaggattgg cccaccgatt ggccagtgat ggaggccgcg 1800aacccgcaga
tccatgggat aggaggggga attcccatgc gaaaatctcg tgacatgata 1860gagttggggg
ttattaaccg agacgggtct ttggagcgac ccctgctcct cttccccgca 1920gtagctatgg
ttagagggag tatcctagga agagattgtc tgcagggcct agggctccgc 1980ttgacaaatt
tatagggagg gccactgttc tctag
2015333063DNAArtificial SequenceChimeric sequences 33atggaagccg
tcataaaggt gatttcgtcc gcgtgtaaaa cctattgcgg gaaaacctct 60ccttctaaga
aggaaatagg ggccatgttg tccctcttac aaaaggaagg gttgcttatg 120tctccctcag
acttatattc cccggggtcc tgggatccca ttaccgcggc gctatcccag 180cgggctatga
tacttgggaa atcgggagag ttaaaaacct ggggattggt tttgggggca 240ttgaaggcgg
ctcgagagga acaggttaca tctgagcaag caaagttttg gttgggatta 300gggggaggga
gggtctctcc cccaggtccg gagtgcatcg agaaaccagc aacggagcgg 360cgaatcgaca
aaggggagga agtgggagaa acaactgtgc agcgagatgc gaagatggcg 420ccggaggaaa
cggccacacc taaaaccgtt ggcacatcct gctatcattg cggaacagct 480attggctgta
attgcgccac agcctcggct cctcctcctc cttatgtggg gagtggtttg 540tatccttccc
tggcgggggt gggagagcag cagggccagg ggggtgacac acctccgggg 600gcggaacagt
caagggcgga gccagggcat gcgggtcagg ctcctgggcc ggccctgact 660gactgggcaa
gggtcaggga ggagcttgcg agtactggtc cgcccgtggt ggccatgcct 720gtagtgatta
agacagaggg acccgcttgg acccctctgg agccaaaatt gatcacaaga 780ctggctgata
cggtcaggac caagggctta cgatccccga ttactatggc agaagtggaa 840gcgcttatgt
cctccccgct gctgccgcat gacgtcacga atctaatgag agttatttta 900gggcctgccc
catatgcctt atggatggac gcttggggag tccaactcca gacagttata 960gcggcagcca
ctcgcgaccc ccgacaccca gcgaacggtc aagggcgggg ggaacggact 1020aatttgaatc
gcttaaaggg cttagctgat gggatggtgg gcaacccaca gggtcaggcc 1080gcattattaa
gaccggggga attggttgct attacggcgt cggctctcca ggcgtttaga 1140gaggttgccc
ggctggcgga acctgcaggt ccatgggcgg acatcatgca gggaccatct 1200gagtcctttg
ttgattttgc caatcggctt ataaaggcgg ttgaggggtc agatctcccg 1260ccttccgcgc
gggctccggt gatcattgac tgctttaggc agaagtcaca gccagatatt 1320cagcagctta
tacggacagc accctccacg ctgaccaccc caggagagat aattaaatat 1380gtgctagaca
ggcagaagac tgcccctctt acggatcaag gcatagccgc ggccatgtcg 1440tctgctatcc
agcccttaat tatggcaggt gctgcaggtc gagagtgtcg tagaaagaag 1500aaagaatatg
tgaaatgttt agaaaacaga gtggcagtgc ttgaaaatca aaacaagaca 1560ttgattgagg
agctaaaagc acttaaggac ctttactgcc acaaatcaga tggtgctgca 1620ggtccagcag
tatcacttgc aatgacaggt gctgcaggtg tggacacgga aagcccactc 1680tgccccctct
ccccactcga ggccggcgat ctagagagcc cgttatctga agagttcctg 1740caagaaatgg
gaaacatcca agagatttcg caatccatcg gcgaggatag ttctggaagc 1800tttggcttta
cggaatacca gtatttagga agctgtcctg gctcagatgg ctcggtcatc 1860acggacacgc
tttcaccagc ttcgagcccc tcctcggtga cttatcctgt ggtccccggc 1920agcgtggacg
agtctcccag tggagcattg aacatcgaat gtagaatctg cggggacaag 1980gcctcaggct
atcattacgg agtccacgcg tgtgaaggct gcaagggctt ctttcggcga 2040acgattcgac
tcaagctggt gtatgacaag tgcgaccgca gctgcaagat ccagaaaaag 2100aacagaaaca
aatgccagta ttgtcgattt cacaagtgcc tttctgtcgg gatgtcacac 2160aacgcgattc
gttttggacg aatgccaaga tctgagaaag caaaactgaa agcagaaatt 2220cttacctgtg
aacatgacat agaagattct gaaactgcag atctcaaatc tctggccaag 2280agaatctacg
aggcctactt gaagaacttc aacatgaaca aggtcaaagc ccgggtcatc 2340ctctcaggaa
aggccagtaa caatccacct tttgtcatac atgatatgga gacactgtgt 2400atggctgaga
agacgctggt ggccaagctg gtggccaatg gcatccagaa caaggaggcg 2460gaggtccgca
tctttcactg ctgccagtgc acgtcagtgg agaccgtcac ggagctcacg 2520gaattcgcca
aggccatccc aggcttcgca aacttggacc tgaacgatca agtgacattg 2580ctaaaatacg
gagtttatga ggccatattc gccatgctgt cttctgtgat gaacaaagac 2640gggatgctgg
tagcgtatgg aaatgggttt ataactcgtg aattcctaaa aagcctaagg 2700aaaccgttct
gtgatatcat ggaacccaag tttgattttg ccatgaagtt caatgcactg 2760gaactggatg
acagtgatat ctcccttttt gtggctgcta tcatttgctg tggagatcgt 2820cctggccttc
taaacgtagg acacattgaa aaaatgcagg agggtattgt acatgtgctc 2880agactccacc
tgcagagcaa ccacccggac gatatctttc tcttcccaaa acttcttcaa 2940aaaatggcag
acctccggca gctggtgacg gagcatgcgc agctggtgca gatcatcaag 3000aagacggagt
cggatgctgc gctgcacccg ctactgcagg agatctacag ggacatgtac 3060tga
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